Interleukin-2 (Aldesleukin, Proleukin, IL-2)
Number: 0024
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
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Criteria for Initial Approval
Aetna considers interleukin-2 (IL-2, Proleukin (aldesleukin)) intravenous medically necessary for the treatment of persons with any of the following conditions:
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Cutaneous melanoma
As high-dose single-agent subsequent therapy for metastatic or unresectable disease; or
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Chronic graft-versus-host disease (GVHD)
For treatment of chronic graft-versus host-disease (GVHD) as additional therapy in conjunction with systemic corticosteroids following no response to first-line therapy options; or
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Neuroblastoma
For treatment of neuroblastoma (see CPB 0895 - Dinutuximab (Unituxin); or
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Renal cell carcinoma
For treatment of metastatic renal cell carcinoma.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
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Renal Cell Carcinoma or Cutaneous Melanoma
Aetna considers continuation of interleukin-2 (IL-2, Proleukin (aldesleukin)) therapy medically necessary for renal cell carcinoma or cutaneous melanoma when all of the following criteria are met:
- The member must be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course; and
- Additional courses of treatment should be given only if there is some tumor shrinkage following the last course; and
- Retreatment is not contraindicated; and
- Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.
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Chronic graft-versus-host disease (GVHD)
Aetna considers continuation of interleukin-2 (IL-2, Proleukin (aldesleukin)) therapy medically necessary for chronic graft-versus-host disease (GVHD) who have improvement in symptoms and no unacceptable toxicity.
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Neuroblastoma
Aetna considers continuation of interleukin-2 (IL-2, Proleukin (aldesleukin)) therapy medically necessary for neuroblastoma when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
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Dosage and Administration
Aldesleukin is available as Proleukin in 22 million IU per single use vial. The recommended Proleukin (aldesleukin) treatment regimen is administered by a 15-minute intravenous infusion every 8 hours. The following schedule has been used to treat adults with metastatic renal cell carcinoma (metastatic RCC) or metastatic melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period. A dose of 600,000 International Units/kg (0.037 mg/kg) is administered every 8 hours by a 15-minute intravenous infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated. During clinical trials, doses were frequently withheld for toxicity. Metastatic RCC individuals treated with this schedule received a median of 20 of the 28 doses during the first course of therapy. Metastatic melanoma individuals received a median of 18 doses during the first course of therapy.
Retreatment: Individuals should be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment should be given to individuals only if there is some tumor shrinkage following the last course and retreatment is not contraindicated. Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.
Source: Clinigen, 2019
Experimental and Investigational
Aetna considers interleukin-2 (IL-2, Proleukin (aldesleukin)) experimental and investigational for the treatment of the following conditions (not an all-inclusive list):
- Acute coronary syndrome
- Acute myeloid leukemia
- Atopic dermatitis
- Autoimmune liver diseases
- Basal cell carcinoma
- Bladder cancer
- Breast cancer / breast cancer lung metastasis
- Candidiasis
- Colorectal cancer
- Cutaneous T-cell lymphoma
- Endometriomas
- HIV infection
- Ischemic heart disease
- Juvenile rheumatoid arthritis
- Malignant pleural effusion
- Mycosis fungoides
- MYH9 (May-Hegglin) platelet disorder
- Nasopharyngeal adenocarcinoma
- Non-small cell lung cancer
- Osteosarcoma lung metastases
- Ovarian cancer
- Pancreatic cancer
- Persons with active, untreated melanoma brain metastases
- Prevention of anemia following radiotherapy or chemotherapy
- Systemic lupus erythematosus
- Tuberculosis
- Wiskott-Aldrich syndrome.
Aetna considers subcutaneous IL-2 experimental and investigational for renal cell carcinoma and all other indications other than intralesional administration of IL-2 for melanoma.
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
- Proleukin is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC).
- Proleukin is indicated for the treatment of adults with metastatic melanoma.
Compendial Uses
- Unresectable cutaneous melanoma
- Chronic graft-versus-host disease (GVHD)
- Neuroblastoma
Note: Interleukin-2 requires inpatient intravenous administration, or outpatient subcutaneous administration. If IL-2 therapy requires hospitalization, it is not medically necessary for the initial length of stay to exceed the number of days of IL-2 administration, typically 5 days or less.
Researchers have found that the immune system may recognize the difference between healthy cells and cancer cells in the body and eliminate those that become cancerous. Cancer may develop when the immune system breaks down or is over-whelmed. Biological therapy (sometimes called immunotherapy, biotherapy, or biological response modifier therapy) uses the body's immune system, either directly or indirectly, to repair, stimulate, or enhance the immune system's natural anticancer function or to lessen side effects that may be caused by some cancer treatments.
Like interferons, interleukins are cytokines that occur naturally in the body and can be made in the laboratory. Although many interleukins (including IL-1 through IL-15) have been identified, interleukin-2 (IL-2) has been the most widely studied in cancer treatment. Interleukin-2, a lymphokine produced by activated T cells, has a wide variety of actions and plays a central role in immune regulation. The primary action of IL-2 is its ability to stimulate the growth of activated T cells that bear IL-2 receptors. Lymphocytes stimulated by IL-2, called lymphokine-activated killer (LAK) cells, have proven to be effective in destroying tumors. Lymphocytes can be removed from a cancer patient's blood, stimulated with IL-2 in the laboratory, and returned to the patient as LAK cells, with the goal of improving the patient's anticancer immune response.
Aldesleukin is available as Proleukin (Clinigen, Inc.) and is an antineoplastic agent and is in the class of response biologic modifiers. It is a recombinant formulation of interleukin‐2 (IL‐2). Proleukin (aldesleukin) is a nonglycosylated biosynthetic interleukin‐2 (also known as T‐cell growth factor), which differs only slightly in amino acid sequence from the natural compound.
Aldesleukin (Proleukin) interacts with the high‐affinity IL‐2 receptor expressed on cells of the immune system and stimulates a cytokine cascade involving various interferons, interleukins, and tumor necrosis factors. Proleukin (aldesleukin) along with other cytokines induce proliferation and differentiation of B and T‐cells, monocytes, macrophages, and cytotoxic lymphocytes which include natural killer (NK) cells, cytotoxic T‐cells, tumor‐infiltrating lymphocytes (TIL), and lymphokine‐activated killer (LAK) cells. The antitumor activity of aldesleukin (Proleukin) is believed to result from activation of cytotoxic lymphocytes, however, the exact mechanism is unknown. Whether aldesleukin (Proleukin) acts directly or through second messengers is also unclear; however, aldesleukin (Proleukin) does elevate production of interleukin‐1, tumor necrosis factors alpha and beta, interferon gamma, and interleukin‐6.
Aldesleukin (Proleukin) is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC) and metastatic melanoma. Patients with advanced renal cell carcinoma (RCC) or advanced melanoma have shown the best response to IL-2 therapy. Response rates for patients with metastatic RCC and metastatic malignant melanoma have been reported as 21 to 38 % and 17 to 26 % respectively, which is as high as or higher than other treatment options. According to available literature, for renal carcinoma, only those who have shown some tumor shrinkage in response to the initial course of IL-2 are considered appropriate candidates for additional treatment. For metastatic melanoma, IL-2 is indicated as a second line treatment in persons who have failed an adequate trial of standard therapy (e.g., dacarbazine alone or in combination with other chemotherapeutic agents).
Intravenous aldesleukin (Proleukin) should be administered in a hospital setting under the supervision of a qualified physician experienced in the use of anticancer agents. Therapy with aldesleukin (Proleukin) for injection should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and formal pulmonary function testing. Extreme caution should be used in patient with a normal thallium stress test and a normal pulmonary function test who have a history of cardiac or pulmonary disease.
Aldesleukin (Proleukin) administration has been associated with capillary leak syndrome (CLS) which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension and reduced organ perfusion which may be severe and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, and mental status changes
Per the prescribing information, aldesleukin (Proleukin) carries the following contraindications in the below settings:
- In patients with an abnormal thallium stress test or abnormal pulmonary function tests (FEV1 >2 liters or ≥75% of predicted for height and age) and those with organ allografts;
- In retreatment and patients who have experienced the following drug related toxicities while receiving an earlier course of therapy:
- Sustained ventricular tachycardia (≥5 beats)
- Cardiac arrhythmias not controlled or unresponsive to management
- Chest pain with ECG changes, consistent with angina or myocardial infarction
- Cardiac tamponade,
- Intubation for >72 hours,
- Renal failure requiring dialysis >72 hours,
- Coma or toxic psychosis lasting >48 hours,
- Repetitive or difficult to control seizures,
- Bowel ischemia/perforation, and/or
- GI bleeding requiring surgery.
Per prescribing information, aldesleukin (Proleukin) carries the following warnings:
- Proleukin administration should be in the hospital setting under supervision of a qualified physician who has experience in the use of anticancer agents;
- Proleukin administration has been associated with capillary leak syndrome (CLS);
- Proleukin treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis;
- Proleukin administration should be withheld in patients developing moderate to severe lethargy or somnolence and continued administration may lead to coma.
Aldesleukin (Proleukin) carries the following common adverse reactions (in > 10% of patients, any grade) (Clinigen, 2019):
- Body as a whole: chills, fever, malaise, asthenia, infection, pain, abdominal pain, abdomen enlarged;
- Cardiovascular: hypotension, tachycardia, vasodilation, supraventricular tachycardia, cardiovascular disorder (i.e., fluctuations in blood pressure, asymptomatic ECG changes, CHF), arrhythmia;
- Digestive: diarrhea, vomiting, nausea, stomatitis, anorexia, and nausea and vomiting;
- Hemic and lymphatic: thrombocytopenia, anemia, leukopenia;
- Metabolic and nutritional disorders: bilirubinemia, creatinine increase, peripheral edema, SGOT increase, weight gain, edema, acidosis, hypomagnesemia, hypocalcemia, alkaline phosphatase increase;
- Nervous: confusion, somnolence, anxiety, dizziness;
- Respiratory: dyspnea, lung disorder (i.e,, physical findings associated with pulmonary congestion, rales, rhonchi), respiratory disorder (i.e., ARDS, CXR infiltrates, unspecified pulmonary changes), cough increase, rhinitis;
- Skin and appendages: rash, pruritis, exfoliative dermatitis;
- Urogenital: oliguria.
Graft Versus Host Disease (GVHD)
Koerth and colleagues (2011) hypothesized that low-dose IL-2 could preferentially enhance regulatory T (Treg) cells in vivo and suppress clinical manifestations of chronic graft-versus-host disease (GVHD). In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous IL-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive IL-2 for an extended period. A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of IL-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than 8 times the baseline value (p < 0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than 5 times the baseline value (p < 0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (p < 0.001 for both comparisons with baseline values), then declined when the patients were not receiving IL-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received IL-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60 % (range of 25 to 100 %). The authors concluded that daily low-dose IL-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients.
In an editorial that accompanied the afore-mentioned study, Bluestone (2011) stated that "future trials involving larger numbers of patients and appropriate control groups are needed to determine the efficacy of not only interleukin-2 therapy but also other approaches to improving Treg numbers and function in autoimmune diseases and GVHD and inhibiting them in cancer. The design of these trials will need to take into account the challenge of interpretation of data in patients who are receiving complex therapies".
Kidney Cancer
In a prospective, multi-center, randomized controlled study, Atzpodien et al (2005) examined the role of adjuvant outpatient immuno-chemotherapy administered post-operatively in high-risk patients with RCC. A total of 203 patients (status post radical tumor nephrectomy) were stratified into 3 risk groups:- subjects with tumor extending into renal vein/vena cava or invading beyond Gerota's fascia (pT3b/c pN0 or pT4pN0),
- subjects with loco-regional lymph node infiltration (pN+), and
- subjects following complete resection of tumor relapse or solitary metastasis (R0).
Patients were randomized to undergo either:
- 8 weeks of outpatient subcutaneous IL-2 (sc-rIL-2), subcutaneous interferon-alpha2a (sc-rIFN-alpha2a), and intravenous 5-fluorouracil (iv-5-FU) according to the standard Atzpodien regimen or
- observation.
Two-, 5-, and 8-year survival rates were 81, 58, and 58 % in the treatment arm, and 91, 76, and 66 % in the observation arm (log rank p = 0.0278), with a median follow-up of 4.3 years. Two, 5-, and 8-year relapse-free survival rates were calculated at 54, 42, and 39 % in the treatment arm, and at 62, 49, and 49 % in the observation arm (log rank p = 0.2398). Stage-adapted sub-analyses revealed no survival advantages of treatment over observation, as well. These findings established that there was no relapse-free survival benefit and the overall survival was inferior with an adjuvant 8-week-outpatient sc-rIL-2/sc-rIFN-alpha2a/iv-5-FU-based immuno-chemotherapy compared to observation in high-risk RCC patients following radical tumor nephrectomy.
In a phase III clinical study, McDermott et al (2005) ascertained the value of outpatient IL-2 and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic RCC. Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m2 subcutaneously every 8 hrs for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m2 subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. A total of 192 patients were enrolled. Toxicities were as anticipated for these regimens. The response rate was 23.2 % (22 of 95 patients) for HD IL-2 versus 9.9 % (9 of 91 patients) for IL-2/IFN (p = 0.018). Ten patients receiving HD IL-2 were progression-free at 3 years versus 3 patients receiving IL-2 and IFN (p = 0.082). The median response durations were 24 and 15 [corrected] months (p = 0.18) [corrected] and median survivals were 17.5 and 13 months (p = 0.24). For patients with bone or liver metastases (p = 0.001) or a primary tumor in place (p = 0.040), survival was superior with HD IL-2. These investigators concluded that this study provided additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic RCC.
Filippetti and colleagues (2009) noted that BRIIL-2 is a clinical study for assessing the effectiveness and toxicity of third-line treatment of pulmonary metastasis from renal cancer and melanoma with flexible bronchoscopic instillation of IL-2. Moreover, these investigators evaluated local and peripheral lymphocytic activation during this IL-2 administration. A total of 2 patients with pulmonary metastasis from renal cancer already treated with two lines of molecular therapy, chemotherapy or systemic immunotherapy were included in this study. With regard to immunological stimulation, lymphocytic fraction decreased from 21 % to 2 % in the first patient and from 10.5 % to 6 % in the second patient, indicating lymphocytic enrollment for activation, while TCD4/CD8 ratio is stable. In both patients, these researchers also observed a significant increase of HLA-DR in T lymphocytes (CD3) either in local or in peripheral blood. No significant toxicities were observed following broncho-instillation, even if the dose was progressively increased. The authors concluded that IL-2 broncho-instillation could represent a valid administration modality to obtain an effective immunological stimulation (either local or systemic).
Melanoma
In a multi-center, phase III clinical trial, Keilholz and associates (2005) examined whether IL-2 as a component of chemo-immunotherapy influences survival of patients with metastatic melanoma. Patients with advanced metastatic melanoma were randomly assigned to receive dacarbazine 250 mg/m2 and cisplatin 30 mg/m2 on days 1 to 3 combined with interferon-alfa-2b 10 x 106 U/m2 subcutaneously on days 1 through 5 without (arm A) or with (arm B) a high-dose intravenous decrescendo regimen of IL-2 on days 5 through 10 (18 x 106 U/m2/6 hrs, 18 x 106 U/m2/12 hrs, 18 x 106 U/m2/24 hrs, and 4.5 x 106 U/m2 for 3 x 24 hrs). Treatment cycles were repeated in the absence of disease progression every 28 days to a maximum of four cycles. A total of 363 patients with advanced metastatic melanoma were accrued. The median survival was 9 months in both arms, with a 2-year survival rate of 12.9 % and 17.6 % in arms A and B, respectively (p = 0.32; hazard ratio, 0.90; 95 % confidence interval [CI[: 0.72 to 1.11). There was also no statistically significant difference regarding progression-free survival (median, 3.0 versus 3.9 months) and response rate (22.8 % versus 20.8 %). These investigators concluded that despite its activity in melanoma as a single agent or in combination with interferon-alfa-2b, the chosen schedule of IL-2 added to the chemo-immunotherapy combination had no clinically relevant activity.
In a Cochrane review, Sasse and colleagues (2007) compared the effects of treatment with chemotherapy and immunotherapy (chemo-immunotherapy) versus chemotherapy alone in patients with metastatic malignant melanoma. These researchers failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic melanoma. They stated that further use of chemo-immunotherapy should only be done in the context of clinical trials.
Weide et al (2010) noted that systemic high-dose IL-2 achieved long-term survival in a subset of patients with advanced melanoma. The authors reported previously that intra-tumorally applied IL-2 induced complete local responses of all metastases in greater than 60 % of patients. The objectives of the current study were to confirm those results in a larger cohort and to identify patient or regimen characteristics associated with response. Patients with melanoma who had a median of 12 injectable metastases received intra-tumoral IL-2 treatments thrice-weekly until they achieved clinical remission. The initial dose of 3 MIU was escalated, depending on the individual patient's tolerance. Forty-eight of 51 patients were evaluable. Only grade 1/2 toxicity was recorded. A complete response that lasted greater than or equal to 6 months was documented in 70 % of all injected metastases. A complete local response of all treated metastases was achieved in 33 patients (69 %), including 11 patients who had between 20 and 100 metastases. Response rates were higher for patients who had stage III disease compared with patients who had stage IV disease. No objective responses of distant untreated metastases were observed. The 2-year survival rate was 77 % for patients with stage IIIB/IIIC disease and 53 % for patients with stage IV disease. Efficacy and survival did not differ between patients who had greater than or equal to 20 lesions and patients who had less than 20 lesions. The authors concluded that intra-tumoral IL-2 treatment elicited complete local responses in a high percentage of patients. They stated that further studies are needed to examine the mode of action of this treatment and its impact on survival.
Other Indications
Researchers are investigating the benefits of IL-2, used alone or with other treatments, in other cancers such as colorectal cancer, ovarian cancer, and small cell lung cancer in ongoing clinical trials. Combinations of IL-2 with other treatment methods such as chemotherapy, surgery, or other biological response modifiers are also under study.
Grande et al (2006) stated that IL-2 has been used to stimulate the immune system for the treatment of multiples tumors. The authors reviewed the reports published from 1990 to 2004 on the IL-2 treatment of tumors other than melanoma and renal carcinoma. They concluded that adjuvant IL-2 may be of value in early stages combined with standard treatment for colon and pancreas cancers. In other neoplasms, the indication for adjuvant IL-2 has been sporadic and does not allow conclusions to be drawn. Assessment of the efficacy of IL-2 combined with chemotherapy as treatment for advanced stages is complex, due to the lack of a control, and the variety of dosages and schemes. The activity of IL-2 in monotherapy or in association with immunotherapy is clinically relevant in hepatocarcinoma, mesothelioma and in malignant overflows as palliative treatment. The authors noted that randomized studies are needed to draw conclusions about its indication in other tumors.
Zlotta and Schulman (2000) stated that for over 2 decades, superficial bladder tumors have been demonstrated to be sensitive to several biological response modifiers and especially to immunomodulators. The best-known and studied immunomodulator is the bacillus Calmette-Guérin (BCG). However, despite its well-recognized effectiveness, BCG is not a panacea and is associated with potentially significant adverse events. New perspectives in BCG therapy aiming to increase BCG efficacy or to decrease side effects include the use of genetically engineered BCG strains producing cytokines as well as the use of purified BCG subcomponents. Because a cascade of immunological reactions including the secretion of several cytokines has been demonstrated in the BCG mode of action, many other biological response modifiers and especially immunomodulators have been studied for superficial transitional cell carcinoma therapy. Some were investigated in human trials, others are still in laboratory studies; some are administered intravesically whereas others are given orally. Intravesical instillations of Interferon-alpha (IFN-alpha) have been evaluated in several controlled studies. Although toxicity of intravesical IFN is minimal, its optimal dose, schedule and effectiveness remain to be defined. Recent prospective studies comparing IFN to BCG intravesical therapy have been somewhat disappointing although this cytokine may be effective in some patients with mucosally confined [T(a)]-papillary or sessile tumors extending into the lamina propria [T(1)] disease who have failed BCG therapy. Other immunomodulators administered intravesically investigated in clinical studies include IL-2, levamisole, Rubratin, and keyhole limpet hemocyanin. Several biological response modifiers administered orally such as vitamin A (and its derivatives), Lactobacillus casei or bropirimine have been tested in clinical trials as well. In contrast, Allium sativum (garlic) or OK-432 (a streptococcal preparation) or BCG sub-fractions have been tested in laboratory studies only. The authors concluded that published reports on several of these biological response modifiers suggest that these compounds may be an alternative in patients with superficial bladder cancer who have failed or have not tolerated BCG, but further evaluation to improve effectiveness, durability and understand their mechanism of action is warranted.
In addition, the National Cancer Institute's Drug Information on aldesleukin (2008) do not include bladder cancer as an established indication.
The drug compendium Clinical Pharmacology (Elsevier/Gold Standard) has recommended off-label use of aldesleukin for mycosis fungoides and cutaneous T-cell lymphoma.
Kolitz (2006) stated that biological therapies, including monoclonal antibodies, peptide vaccines and IL-2, are undergoing evaluation for the treatment of acute myeloid leukemia. Dummer (2006) noted that therapies under investigation for the treatment of cutaneous T-cell lymphoma include topical retinoids, fusion molecules like denileukin diftitox (ONTAK), pegylated interferon, IL-2, and IL-12.
Interleukin-2 has been studied in HIV since the early days of the epidemic. Researchers have found that IL-2 administered in low doses appears to activate natural killer cells, and at high intermittent doses, it appears to be a potent T-cell growth factor, resulting in large and sustained increases in CD4+ cell counts, which may take upwards of 6 months to occur. However, IL-2 has not been shown to improve survival of HIV-infected patients.
Guidelines from the Centers for Disease Control and Prevention (CDC, 2008) state that interleukin-2 has demonstrated robust and sustained CD4 T-cell count increases in some studies. The guidelines note, however, that controversy persists as to how much enhancement of immune function occurs. The guidelines state that, "with this controversy, drug-associated side effects, and the need for parenteral administration, this strategy cannot be recommended unless with enrollment into a clinical trial".
Two randomized clinical studies have provided definitive evidence of the lack of effectiveness of IL-2 in HIV infection. The INSIGHT-ESPRIT Study Group and the SILCAAT Scientific Committee (Abrams et al, 2009) noted that when used in combination with anti-retroviral therapy (ART), subcutaneous recombinant IL-2 raises CD4+ cell counts more than does ART alone. However, the clinical implication of these increases is not known. These investigators conducted 2 trials:- the subcutaneous recombinant, human IL-2 in HIV-infected patients with low CD4+ counts under active ART (SILCAAT) study, and
- the evaluation of subcutaneous proleukin in a randomized international trial (ESPRIT).
In each trial, patients infected with the HIV who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive IL-2 plus ART or ART alone. The IL-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved 6 cycles and a dose of 4.5 million international units [MIU] of IL-2 twice-daily; ESPRIT involved 3 cycles and a dose of 7.5 MIU twice-daily. Additional cycles were recommended to maintain the CD4+ cell count above pre-defined target levels. The primary end point of both studies was opportunistic disease or death from any cause. In the SILCAAT study, 1,695 patients (849 receiving IL-2 plus ART and 846 receiving ART alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4,111 patients (2,071 receiving IL-2 plus ART and 2,040 receiving ART alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the IL-2 group than in the group receiving ART alone -- by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with IL-2 plus ART (versus ART alone) were 0.91 (95 % CI: 0.70 to 1.18; p = 0.47) in the SILCAAT study and 0.94 (95 % CI: 0.75 to 1.16; p = 0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (p = 0.73) and 1.10 (p = 0.35), respectively, in the SILCAAT study and 0.90 (p = 0.42) and 1.23 (p = 0.003), respectively, in ESPRIT. The authors concluded that despite a substantial and sustained increase in the CD4+ cell count, as compared with ART alone, IL-2 plus ART yielded no clinical benefit in either study. An editorialist (Gandhi, 2009) commented that "these large studies demonstrate that although IL-2 raises CD4-cell counts, it does not improve clinical outcomes".
In a randomized, open-label, multi-center controlled trial, Viard and colleagues (2009) evaluated the efficacy of adding IL-2 to an optimized background treatment in HIV-1 patients with advanced failure. Patients with CD4 T-cell count of less than 200 cells/microl, plasma HIV-1 RNA of more than 10 000 copies/ml and a genotypic sensitivity score showing 2 or less active drugs were randomized to either 8 IL-2 cycles with optimized background treatment or optimized background treatment alone. Optimization was made according to genotypic sensitivity score. Enfuvirtide was added in enfuvirtide-naive patients. Evaluation was performed at week 52 on the proportions of patients with CD4 cell count of at least 200 cells/microl (primary outcome), of patients with a CD4 cell count increase of at least 50 cells/microl from week 0, on plasma HIV-1 RNA and HIV-related events. A total of 56 patients were analyzed. Median age was 43 years, 61 % were at Center for Disease Control and Prevention stage C, 43 % had a genotypic sensitivity score of 0, median baseline CD4 cell count and plasma HIV-1 RNA values were 64 cells/microl and 4.9 log10 copies/ml, respectively. Treatment could be optimized in 23 patients. At week 52, in the IL-2 and control groups, the proportion of patients with CD4 cell count of at least 200 cells/microl (14 % and 18 %) or a CD4 cell count increase of at least 50 cells/microl (25 % and 32 %) and median plasma HIV-1 RNA were not significantly different. In multi-variate analysis, optimization with enfuvirtide and baseline CD4 cell count were statistically associated with CD4 cell count of at least 200 cells/microl at week 52 (p = 0.003 and p = 0.01). Optimization with enfuvirtide was the only factor associated with a CD4 cell count gain of at least 50 cells/microl (p < 0.001). There was no difference in the rate of AIDS events between groups. The authors concluded that IL-2 failed to increase CD4 cell count in immunocompromised patients with multiple therapeutic failures; while use of enfuvirtide was highly associated with success.
Acien and colleagues (2010) analyzed the therapeutic results of rIL-2 left in the cysts after trans-vaginal ultrasound (US)-guided drainage of endometriomas as an alternative to surgery. A total of 25 consecutive patients were included. Two trans-vaginal US-guided punctures were performed, and 3 MIU of rIL-2 were left in the aspirated cysts once (group I) or both (group II) times according to randomization. Main outcome measures included clinical results, prevented surgeries, and recurrences. Results were moderate or good in only 16 % of subjects at 3 months and in 33 % of subjects at 6 months after treatment in group I; these numbers were 66 % and 33%, respectively, in group II. Differences were not statistically significant. However, the evolution of symptoms, endometriomas, and CA-125 revealed the low efficacy of rIL-2 left intra-cyst as well as a poor control of the clinical manifestations. After 1 year, 20 % (group I) and 73 % (group II) of patients had to be operated; after 2 years, these numbers were 55 % and 82 %, respectively. The authors concluded that treatment of endometriomas with trans-vaginal US-guided drainage and rIL-2 left in the cysts, without using endometrial suppressive therapy with gonadotropin-releasing hormone analogs as done in previous studies, has low efficacy. Furthermore, recurrences are even more frequent after the use of 2 rIL-2 doses.
Buyse et al (2011) stated that IL-2 monotherapy has been evaluated in several randomized clinical trials (RCTs) for remission maintenance in patients with acute myeloid leukemia (AML) in first complete remission (CR1), and none demonstrated a significant benefit of IL-2 monotherapy. The objective of this meta-analysis was to reliably determine IL-2 efficacy by combining all available individual patient data (IPD) from 5 RCTs (n = 905) and summary data from a 6th RCT (n = 550). Hazard ratios (HRs) were estimated using Cox regression models stratified by trial, with HR less than 1 indicating treatment benefit. Combined IPD showed no benefit of IL-2 over no treatment in terms of leukemia-free survival (HR = 0.97; p = 0.74) or overall survival (HR = 1.08; p = 0.39). Analyses including the 6th RCT yielded qualitatively identical results (leukemia-free survival HR = 0.96, p = 0.52; overall survival HR = 1.06; p = 0.46). No significant heterogeneity was found between the trials. Pre-specified subset analyses showed no interaction between the lack of IL-2 effect and any factor, including age, sex, baseline performance status, karyotype, AML subtype, and time from achievement of CR1 to initiation of maintenance therapy. The authors concluded that IL-2 alone is not an effective remission maintenance therapy for AML patients in CR1.
Pistoia et al (2011) stated that cytokines released by cancer cells or by cells of the tumor microenvironment stimulate angiogenesis, act as autocrine or paracrine growth factors for malignant cells, promote tumor cell migration and metastasis or create an immunosuppressive microenvironment. These tumor-promoting effects of cytokines also apply to neuroblastoma (NB), a pediatric neuroectodermal malignancy with frequent metastatic presentation at diagnosis and poor prognosis. IL-6 and VEGF are the best characterized cytokines that stimulated tumor growth and metastasis, while others such as IFN-γ can exert anti-NB activity by inducing tumor cell apoptosis and inhibiting angiogenesis. On the other hand, cytokines are part of the anti-NB therapeutic armamentarium, as exemplified by IL-2 and granulocyte-macrophage colony stimulating factor that potentiate the activity of anti-NB antibodies. These recent results raise hope for more efficacious treatment of this ominous pediatric malignancy.
The prescribing information for Proleukin notes the lack of efficacy of low dose aldesleukin regimens, which are administered subcutaneously. The prescribing information describes the results of a single-center, open label, non-randomized trial involving 65 patients with metastatic renal cell cancer that sequentially evaluated the safety and anti-tumor activity of two low dose aldesleukin regimens. The regimens administered 18 million International Units aldesleukin as a single subcutaneous injection, daily for 5 days during week 1; aldesleukin was then administered at 9 x106 International Units days 1-2 and 18 x106 International Units days 3-5, weekly for an additional 3 weeks (n=40) followed by a 2 week rest or 5 weeks (n=25) followed by a 3 week rest, for a maximum of 3 or 2 treatment cycles, respectively. The prescribing information states that these low dose regimens yielded substantially lower and less durable responses than those observed with the approved regimen. The prescribing information states that, based on the level of activity, these low dose regimens are not effective.
In a multi-center, open-label, randomized phase III trial, Correale et al (2014) compared the immunobiological activity and anti-tumor effectiveness of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive bi-weekly standard FOLFOX-4 or GOLFIG [gemcitabine (1,000 mg/m(2), day 1); oxaliplatin (85 mg/m(2), day 2); levofolinate (100 mg/m(2), days 1 to 2), 5-fluorouracil (5-FU) (400 mg/m(2) in bolus followed by 24-hr infusion at 800 mg/m(2),days 1 to 2), sc. GM-CSF (100 μg, days 3 to 7); sc. aldesleukin (0.5 MIU bi-daily, days 8 to 14 and 17 to 30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9·23 (95 % CI: 6.9 to 11.5) versus median 5.70 (95 % CI: 3.38 to 8.02) months; HR: 0.52 (95 % CI: 0.35 to 0.77), p = 0·002] and response rate [66.1 % (95 % CI: 0.41 to 0.73) versus 37.0 % (95 % CI: 0.28 to 0.59), p = 0.002], with a trend to longer survival [median 21.63 (95 % CI: 18.09 to 25.18) versus 14.57 mo (95 % CI: 9.07 to 20.07); HR: 0.79 (95 % CI: 0.52 to 1.21); p = 0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5 %), autoimmunity signs (18.5 %), an increase in the number of monocytes, eosinophils, CD4(+) T-lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3(+)CD4(+)CD25(+)FoxP3(+)) T cells. The authors concluded that taken together, these findings provided proof-of-principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC.
An UpToDate review on “Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach” (Clark and Sanoff, 2022) does not mention interleukin-II as a therapeutic option.
Furthermore, NCCN's clinical practice guidelines on “Colon cancer” (Version 1.2022) and “Rectal cancer” (Version 1.2022) do not mention interleukin-II as a therapeutic option.
Prevention of Anemia Following Radiotherapy or Chemotherapy
Chopra et al (2015) stated that mice deficient in IL-2 signaling develop severe anemia indicating a defect in erythropoiesis. However, why deficiency in IL-2, an essential growth factor for lymphocytes, or in IL-2 signaling components should result in defective erythropoiesis is unclear. These researchers analyzed the mechanism of IL-2 signaling deficiency-induced anemia in mice and showed that IL-2 plays an indispensable role in bone marrow erythropoiesis via maintenance of regulatory T cells (Treg ). In absence of IL-2 signaling, interferon-gamma (IFN-γ) produced by the activated T cells suppressed klf1 expression, resulting in an early block in erythrocyte differentiation. Anemia, in IL-2 or IL-2 signaling-deficient mice always developed prior to the manifestation of other autoimmune complications like colitis, suggesting that anemia in these mice might be a contributing factor in inducing other pathological complications in later stages. These investigators noted that their study showed how essential cytokines of lymphoid cells could exert critical influence on the development of erythrocytes and thus expanding the understanding of the complex regulation of hematopoiesis in the bone marrow. Furthermore, the authors stated that their findings might facilitate the use of IL-2 and anti-IFN-γ as a clinical remedy against anemia that arise in cancer patients following radiotherapy or chemotherapy, a context which simulates the situation of IL-2 deficiency.
Systemic Lupus Erythematosus
von Spee-Mayer et al (2016) noted that defects in Treg biology have been associated with human systemic autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the origin of such Treg defects and their significance in the pathogenesis and treatment of SLE are still poorly understood. Peripheral blood mononuclear cells (PBMC) from 61 patients with SLE and 52 healthy donors and in-vitro IL-2 stimulated PBMC were characterized by multi-color flow cytometry. A total of 5 patients with refractory SLE were treated daily with subcutaneous injections of 1.5 million IU of aldesleukin for 5 consecutive days, and PBMC were analyzed by flow cytometry. Patients with SLE develop a progressive homeostatic dysbalance between Treg and conventional CD4+ T cells in correlation with disease activity and in parallel display a substantial reduction of CD25 expression on Treg. These Treg defects resembled hallmarks of IL-2 deficiency and led to a markedly reduced availability of functionally and metabolically active Treg. In-vitro experiments revealed that lack of IL-2 production by CD4+ T cells accounted for the loss of CD25 expression in SLE Treg, which could be selectively reversed by stimulation with low doses of IL-2. Accordingly, treatment of patients with SLE with a low-dose IL-2 regimen selectively corrected Treg defects also in-vivo and strongly expanded the Treg population. The authors concluded that Treg defects in patients with SLE are associated with IL-2 deficiency, and can be corrected with low doses of IL-2. These preliminary findings need to be validated by well-designed studies.
Acute Myeloid Leukemia
In a Cochrane review, Mao and colleagues (2015) evaluated the safety and effectiveness of IL-2 as maintenance therapy for children and adults with AML who have achieved first CR and have not relapsed. These researchers systematically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 8), Medline (1950 to August 2015), Embase (1950 to August 2015), LILACS (1982 to August 2015), CBM (1978 to August 2015), relevant conference proceedings (2000 to 2015), and metaRegister of Controlled Trials (since inception to August 2015) of ongoing and unpublished trials. In addition, they screened the reference lists of relevant trials and reviews. Eligible studies were RCTs comparing IL-2 with no treatment in people with AML who had achieved first CR and had not relapsed. These investigators did not identify studies comparing IL-2 versus best supportive care or maintenance chemotherapy or studies comparing IL-2 plus maintenance chemotherapy versus maintenance chemotherapy alone. Two review authors independently screened studies, extracted data with a predefined extraction form, and assessed risk of bias of included studies. They extracted data on the following outcomes: disease-free survival (DFS), overall survival (OS), event-free survival (EFS), treatment-related mortality, adverse events (AEs), and quality of life (QOL). These researchers measured the treatment effect on time-to-event outcomes and dichotomous outcomes with HR and risk ratio (RR), respectively. They used inverse-variance method to combine HRs with fixed-effect model unless there was significant between-study heterogeneity. The authors included 9 RCTs with a total of 1,665 participants, comparing IL-2 with no treatment; 6 studies included adult participants, and 3 studies included both adults and children. However, the latter 3 studies did not report data for children, thus these investigators were unable to conduct subgroup analysis of children. One Chinese study did not report any outcomes of interest for this review. These researchers included 6 trials involving 1,426 participants in the meta-analysis on DFS, and included 5 trials involving 1,355 participants in the meta-analysis on OS. There is no evidence for difference between IL-2 group and no-treatment group regarding DFS (HR 0.95; 95 % CI: 0.86 to 1.06, p = 0.37; quality of evidence: low) or OS (HR 1.05; 95 % CI: 0.95 to 1.16, p = 0.35; quality of evidence: moderate). Based on 1 trial of 161 participants, IL-2 exerted no effect on EFS (HR 1.02; 95 % CI: 0.79 to 1.32, p = 0.88; quality of evidence: low); AEs (including thrombocytopenia, neutropenia, malaise/fatigue, and infection/fever) were more frequent in participants receiving IL-2, according to 1 trial of 308 participants. No mortality due to AEs was reported; none of the included studies reported treatment-related mortality or QOL. The authors concluded that there is no evidence for a difference between IL-2 maintenance therapy and no treatment with respect to DFS or OS of people with AML in first CR; however, the quality of the evidence was moderate or low, and further research is likely or very likely to have an important impact on the estimate or the confidence in the estimate. They stated that AEs appeared to be more frequent in participants treated with IL-2, but the quality of the evidence was very low and the confidence in the estimates was very uncertain. Thus, they stated that further prospective randomized trials are needed before definitive conclusions can be drawn on these issues.
Basal Cell Carcinoma
Sobjanek and colleagues (2016) stated that basal cell carcinoma (BCC) is an immunogenic neoplasm and the imbalance in Th1/Th2 cytokines expression appears to play the major role in pathogenesis and clinical behavior of the tumor. These researchers examined the association of soluble IL-2α receptor (sIL-2Rα) and IL-2 serum concentrations with BCC. The study entailed 110 individuals with BCC and 60 healthy age- and sex-matched volunteers; serum levels of sIL-2Rα and IL-2 were measured using ELISA test. These investigators found significantly (p = 0.027) increased sIL-2Rα serum levels in BCC patients, in comparison to healthy controls. Statistically (p = 0.04) higher sIL-2Rα levels were observed in patients with more advanced tumors. Serum levels of sIL-2Rα showed a significant linear (r = 0.24, p = 0.018) correlation with tumor size. The average IL-2 serum levels in BCC patients were statistically (p = 0.039) decreased compared to controls. Significantly (p = 0.0454) lower median IL-2 levels were observed in patients with more advanced tumors. A negative correlation between sIL-2Rα and IL-2 serum concentrations was revealed (r = -0.22; p = 0.027). The authors concluded that these findings testified to the importance of the IL-2/sIL-2Rα signaling pathway in pathogenesis of BCC, suggesting that IL-2 and sIL-2Rα might be considered as potential markers of disease and targets for immunotherapy in BCC patients.
UpToDate reviews on “Treatment and prognosis of basal cell carcinoma at low risk of recurrence” (Aasi, 2022), “Treatment of basal cell carcinomas at high risk for recurrence” (Aasi and Hong, 2021), and “Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas” (Martins, 2022) do not mention IL-2 as therapeutic option.
Neuroblastoma
Levy and associates (2015) stated that recombinant IL-2 is used with ch14.18/CHO to improve the cytotoxic activity of NK lymphocytes against neoplastic cells. The effectiveness of this treatment is limited by its potential side effects. These investigators reported an unusual case of necrotizing enterocolitis associated with the administration of IL-2 and ch14.18/CHO in maintenance therapy for localized NMyc amplified neuroblastoma (NBL). This case high-lighted the potentially significant toxicity of this immunotherapy that is currently being tested in the high-risk NBL-1.5 protocol. Further, short-term, medium-term, and long-term follow-up in this patient population are needed to judge the potential benefit of this treatment versus the short-term, medium-term, and long-term side effects in a patient population with an outcome that is better than that of stage 4 NBL patients.
An UpToDate review on "Treatment and prognosis of neuroblastoma" (Shohet et al, 2022) makes the following recommendation for high-risk disease:
Maintenance: "The addition of dinutuximab plus cytokines (GM-CSF and IL-2) was found to have benefit over cis-retinoic acid alone for prevention of recurrence in a randomized trial. The immunotherapy approach resulted in superior two-year two-year event-free and overall survival rates (66 versus 46 percent, and 86 versus 75 percent, respectively). Toxicities include serious and potentially life-threatening infusion reactions, and severe neuropathic pain."
Nasopharyngeal Adenocarcinoma
Hsu and Hsu (1989) sought beneficial immunomodulation with IL-2 for patients with nasopharyngeal carcinoma (NPC); a study was conducted of the response to and concentration of IL-2 by mononuclear cells (MNC) from 45 NPC patients who had been pathologically verified, but pre-treatment, at the time they were studied; 38 normal healthy controls were studied simultaneously. Lymphocyte subsets did not change much after IL-2 stimulation in either NPC patients or the controls. A decreased IL-2 concentration was found in NPC, and a trend of inverse correlation to clinical staging was detected; the more advanced stage, the less concentration of IL-2. The authors concluded that there was a normal response to and decreased concentration of IL-2 in NPC patients. Whether decreased concentration of IL-2 in NPC patients resulted from decreased production or increased consumption is unclear. They stated that further research of IL-2 immunomodulation in NPC patients should be done before its clinical application.
In a phase II clinical trial, Chi and colleagues (2001) evaluated the toxicity, effectiveness, and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. Between November 1996 and April 1997, a total of 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin) was injected by intravenous bolus every 8 hours at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were re-treated with a 2nd identical cycle of therapy. Those patients who were stable or responding to treatment 5 to 6 weeks later went on to receive another course (2 cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-alpha, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. A total of 14 patients received a total of 34 cycles of therapy. No response was observed; 50 % had stable disease, 50 % had progressive disease after a median of 2 cycles of therapy. There was 1 treatment-related death from acute myocardial infarction. Body weight increase (greater than 5 %) occurred in 80 % of cycles, and hypotension (BP less than 80 mm Hg systolic) occurred in 53 %. Serum creatinine increase (greater than 2 mg %) occurred in 24 % of cycles, and SGOT/SGPT increase (greater than 3x) in 10 % of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, as well as desquamation were generally mild-to-moderate but rapidly reversible. The authors concluded that the single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients.
Autoimmune Liver Diseases
Jeffery and colleagues (2017) noted that CD4+ CD25high CD127low fork-head box protein 3 (FoxP3+ ) regulatory T cells (Treg ) are essential for the maintenance of peripheral tolerance. Impaired Treg function and an imbalance between effector and Tregs contribute to the pathogenesis of autoimmune diseases. These investigators recently reported that the hepatic microenvironment is deficient in IL-2, a cytokine essential for Treg survival and function. Consequently, few liver-infiltrating Treg demonstrate signal transducer and activator of transcription-5 (STAT-5) phosphorylation. To establish the potential of IL-2 to enhance Treg therapy, these researchers examined the effects of very low-dose Proleukin (VLDP) on the phosphorylation of STAT-5 and the subsequent survival and function of Treg and T effector cells from the blood and livers of patients with autoimmune liver diseases. VLDP, at less than 5 IU/ml, resulted in selective phosphorylation of STAT-5 in Treg, but not effector T cells or natural killer cells and associated with increased expression of cytotoxic T lymphocyte antigen-4 (CTLA-4), FoxP3 and CD25 and the anti-apoptotic protein Bcl-2 in Treg with the greatest enhancement of regulatory phenotype in the effector memory Treg population. VLDP also maintained expression of the liver-homing chemokine receptor CXCR3. VLDP enhanced Treg function in a CTLA-4-dependent manner. The authors concluded that these findings opened new avenues for future VLDP cytokine therapy alone or in combination with clinical grade Treg in autoimmune liver diseases, as VLDP could not only enhance regulatory phenotype and functional property but also the survival of intra-hepatic Treg. The authors noted that the findings of this study extended the potential of VLDP therapy to the treatment of autoimmune liver diseases. They stated that these findings provide compelling evidence to support the design of Treg‐directed phase I and II clinical trials administering VLDP as a cytokine monotherapy or in combination with autologous Treg cell therapy in autoimmune liver diseases.
Breast Cancer
Li and colleagues (2017) stated that the precise role of IL-10 in breast cancer is not clear. Previous studies suggested a tumor-promoting role of IL-10 in breast cancer, whereas recent discoveries that IL-10 activated and expanded tumor-resident CD8+ T cells challenged the traditional view. These investigators examined the role of IL-10 in HLA-A2-positive breast cancer patients with Grade III, Stage IIA or IIB in-situ and invasive ductal carcinoma, and compared it with that of IL-2, the canonical CD8+ T cell growth factor. These researchers first observed that breast cancer patients presented higher serum levels of IL-2 and IL-10 than healthy controls. Upon prolonged TCR stimulation, peripheral blood CD8+ T cells from breast cancer patients tended to undergo apoptosis, which could be prevented by the addition of IL-2 and/or IL-10. The cytotoxicity of TCR-activated CD8+ T cells was also enhanced by exogenous IL-2 and/or IL-10. Interestingly, IL-2 and IL-10 demonstrated synergistic effects, since the enhancement in CD8+ T cell function when both cytokines were added was greater than the sum of the improvements mediated by each individual cytokine. IL-10 by itself could not promote the proliferation of CD8+ T cells, but could significantly enhance IL-2-mediated promotion of CD8+ T cell proliferation. In addition, the cytotoxicity of tumor-infiltrating CD8+ T cells in breast tumor was elevated when both IL-2 and IL-10 were present, but not when either one was absent. This synergistic effect was stopped by CD4+CD25+ regulatory T cells (Treg), which depleted IL-2 in a cell number-dependent manner. The authors concluded that these findings demonstrated that IL-2 and IL-10 could work synergistically to improve the survival, proliferation, and cytotoxicity of activated CD8+ T cells, an effect suppressible by CD4+CD25+ Treg cells.
HIV Infection
In a Cochrane review, Onwumeh and colleagues (2017) examined the effects of IL-2 as an adjunct to ART for HIV-positive adults. These investigators searched the following sources up to May 26, 2016: the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; Medline; Embase; the Web of Science; LILACS; the World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP); and ClinicalTrials.gov. They also checked conference abstracts, contacted experts and relevant organizations in the field, and checked the reference list of all studies identified by the above methods for any other potentially eligible studies; RCTs that evaluated the effects of IL-2 as an adjunct to ART in reducing the morbidity and mortality in HIV-positive adults were selected for analysis; 2 review authors independently screened records and selected trials that met the inclusion criteria, extracted data, and assessed the risk of bias in the included trials. Where possible, they compared the effects of interventions using RR, and presented them with 95 % CIs. These researchers assessed the overall certainty of the evidence using the GRADE approach. Following a comprehensive literature search up to May 26, 2016, these investigators identified 25 eligible trials. The interventions involved the use of IL-2 in combination with ART compared with ART alone. There was no difference in mortality apparent between the IL-2 group and the ART alone group (RR 0.97, 95 % CI: 0.80 to 1.17; 6 trials, 6,565 participants, high certainty evidence); 17 of 21 trials reported an increase in the CD4 cell count with the use of IL-2 compared to control using different measures (21 trials, 7,600 participants). Overall, there was little or no difference in the proportion of participants with a viral load of less than 50 cells/ml or less than 500 cells/ml by the end of the trials (RR 0.97, 95 % CI: 0.81 to 1.15; 5 trials, 805 participants, high certainty evidence) and (RR 0.96, 95 % CI: 0.82 to 1.12; 4 trials, 5,929 participants, high certainty evidence) respectively. Overall, there may be little or no difference in the occurrence of opportunistic infections (RR 0.79, 95 % CI: 0.55 to 1.13; 7 trials, 6,141 participants, low certainty evidence). There was probably an increase in grade 3 or 4 AEs (RR 1.47, 95 % CI: 1.10 to 1.96; 6 trials, 6,291 participants, moderate certainty evidence). None of the included trials reported adherence. The authors concluded that there was high certainty evidence that IL-2 in combination with ART increased the CD4 cell count in HIV-positive adults. However, IL-2 did not confer any significant benefit in mortality; there was probably no difference in the incidence of opportunistic infections, and there was probably an increase in grade 3 or 4 AEs. They stated that these findings did not support the use of IL-2 as an adjunct to ART in HIV-positive adults; and based on these findings, further trials are not justified.
Non-Small Cell Lung Cancer
Mi and colleagues (2016) stated that the effectiveness of IL-2 and induced killer cells for non-small cell lung cancer (NSCLC) is controversial. This study evaluated the safety and effectiveness of IL-2 and induced killer cells on NSCLC. Relevant RCTs were searched in Cochrane library (Issue 2, 2013), Web of Science (1980 to March 2013), PubMed (1966 to March 2013), China Knowledge Resource Integrated database (CNKI) (1994 to March 2013), China Biology Medicine database (CBM) (1978 to March 2013), VIP (1989 to March 2013), and Wan Fang databases (1997 to March 2013). There were no language restrictions. After independent quality assessment and data extraction by 2 authors, meta-analysis was conducted by RevMan 5.1 software. A total of 10 RCTs were included. Odds ratio (OR), 95 % CI, p value expressed as test group (IL-2 or induced killer cells combined chemotherapy) versus control group (chemotherapy alone), was 2.02 (1.24 to 3.29; p = 0.004) for disease control rate; HR (95 % CI; p value), expressed as test group (IL-2 or induced killer cells) versus control group, were 0.60 (0.46 to 0.79; p = 0.0003) for overall survival of post-operative treatment, and 0.77 (0.60 to 0.99; p =0.04) for OS of combination with chemotherapy. Mean differences (MD) (95 % CI; p value), expressed as test group (IL-2 or induced killer cells) versus control group (after treatment), were 11.32 (6.32 to 16.33; p = 0.00001) for NK cells, 11.79 (2.71 to 20.86; p = 0.01) for CD3+ cells, 14.63 (2.62 to 26.64; p = 0.02) for CD4+ cells, and -4.49 (-7.80 to 1.18; p = 0.008) for CD8+ cells. The authors concluded that the findings of this meta-analysis showed that IL-2 or induced killer cells combination therapy was effective in treating NSCLC and improved OS. Moreover, they stated that further analysis of trials having adequate information and data are needed to confirm these findings.
The authors noted that this study had several drawbacks:- some RCTs included in this meta-analysis were not adequate as these did not report the detailed method of random sequence generation and concealment of allocation, and all trials did not mention the use of blinding,
- publication bias was a wide phenomenon for all forms of meta-analysis. Although these investigators searched several databases and no publication bias was detected in the funnel plot analysis, publication bias might still be a limitation,
- the standard preparation process of biological drugs, the combination treatment strategies, the effectiveness of different cell types and other issues (dose strategy, timing, individual therapy of histological types, the long-term survival rate) mentioned above should be further explored with a large sample and rigorous clinical research, and
- there were limited data of detail AEs to perform a meta-analysis.
Osteosarcoma Lung Metastases
Dhupkar and Gordon (2017) noted that IL-2 is a very well-known cytokine that has been studied for the past 35 years. It plays a major role in the growth and proliferation of many immune cells such NK and T cells. It is an important immunotherapy cytokine for the treatment of various diseases including cancer. Systemic delivery of IL-2 has shown clinical benefit in renal cell carcinoma and melanoma patients. However, its use has been limited by the numerous toxicities encountered with the systemic delivery. Intravenous IL-2 causes the well-known "capillary leak syndrome" or the leakage of fluid from the circulatory system to the interstitial space resulting in hypotension, edema, and dyspnea. Due to the toxicities associated with systemic IL-2, an aerosolized delivery approach has been developed, which enables localized delivery and a higher local immune cell activation. Since proteins are absorbed via pulmonary lymphatics, after aerosol deposition in the lung, aerosol delivery provides a means to more specifically target IL-2 to the local immune system in the lungs with less systemic effects. Its benefits have extended to diseases other than cancer. Delivery of IL-2 via aerosol or as nebulized IL-2 liposomes has been previously shown to have less toxicity and higher efficacy against sarcoma lung metastases. Dogs with cancer provided a highly relevant means to determine bio-distribution of aerosolized IL-2 and IL-2 liposomes. However, efficacy of single-agent IL-2 was limited. As in general, for most immune-therapies, its effect is more beneficial in the face of minimal residual disease (MRD). To overcome this limitation, combination therapies using aerosol IL-2 with adoptive transfer of T cells or NK cells have emerged. Using a human osteosarcoma (OS) mouse model, these researchers had demonstrated the effectiveness of single-agent aerosol IL-2 and combination therapy aerosol IL-2 and NK cells or aerosol IL-2 and IL-11 receptor alpha-directed chimeric antigen receptor-T cells (IL-11 receptor α CAR-T cells) against OS pulmonary metastases. Combination therapy resulted in a better therapeutic effect. A phase-I clinical trial of aerosol IL-2 was performed in Europe and proved to be safe. Others and these researchers’ pre-clinical studies provided the basis for the development of a phase-I aerosol IL-2 clinical trial in the authors’ institution to include younger patients with lung metastases. Osteosarcoma has a peak incidence in the adolescent and young adult years; these investigators’ goal is to complete this trial in the next 2 years. The authors summarized the different effects of IL-2 and covered the advantages of the aerosol delivery route for diseases of the lung with an emphasis on some of their most recent work using combination therapy aerosol IL-2 and NK cells for the treatment of OS lung metastases.
Ovarian Cancer
Minor and colleagues (2017) reported a 14-year remission of recurrent ovarian cancer with intraperitoneal IL-2). Intraperitoneal IL-2 was given with little toxicity. The authors concluded that immunotherapy may have the potential for durable remissions in ovarian cancer.
Wiskott-Aldrich Syndrome
Jyonouchi and associates (2017) stated that low-dose IL-2 can restore the function of T and NK cells from Wiskott-Aldrich (WAS) patients. However, the safety of in-vivo IL-2 in WAS is unknown. In a phase-I clinical trial, these researchers examined the safety of low-dose IL-2 in WAS. Patients received 5 daily subcutaneous IL-2 injections, every 2 months, for 3 courses. A "3+3" dos- escalation method was used. A total of 6 patients received the 0.5 million units/m2/day dose without serious AEs. However, 2 of 3 patients receiving the 1million units/m2/day dose developed thrombocytopenia requiring platelet transfusions. A statistically significant platelet increase occurred in patients receiving the 0.5 million units/m2/day dose. A trend toward higher T, B and NK cell numbers and higher T regulatory cell percentages was observed. The authors concluded that they had identified a safe IL-2 dose for WAS patients. Moreover, they stated that additional trials are needed to examine the effectiveness of IL-2 as a treatment for patients with WAS.
Acute Coronary Syndrome and Ischemic Heart Disease
Zhao and colleagues (2018) stated that inflammation and dysregulated immune responses play a crucial role in atherosclerosis, underlying ischemic heart disease (IHD) and acute coronary syndromes (ACSs). Immune responses are also major determinants of the post-ischemic injury in myocardial infarction (MI). Regulatory T cells (CD4+CD25+FOXP3+; Treg) induce immune tolerance and preserve immune homeostasis. Recent in-vivo studies suggested that low-dose IL-2 can increase Treg cell numbers. Aldesleukin is a human recombinant form of IL-2 that has been used therapeutically in several autoimmune diseases. However, its safety and efficacy is unknown in the setting of coronary artery disease. LILACS (low-dose IL-2 in patients with stable ischemic heart disease and acute coronary syndromes) is a single-center, first-in-class, dose-escalation, 2-part clinical trial. Patients with stable IHD (part A) and ACS (part B) will be randomized to receive either IL-2 (Aldesleukin; dose range 0.3 to 3×106 IU) or placebo once-daily, given subcutaneously, for 5 consecutive days. Part A will have 5 dose levels with 5 patients in each group. Group 1 will receive a dose of 0.3×106 IU, while the dose for the remaining four groups will be determined on completion of the preceding group. Part B will have 4 dose levels with 8 patients in each group. The dose of the first group will be based on part A. Doses for each of the subsequent 3 groups will similarly be determined after completion of the previous group. The primary end-point is safety and tolerability of Aldesleukin and to determine the dose that increases mean circulating Treg levels by at least 75 %. The trial began on May 15, 2017. The anticipated final follow-up visit(s) will be in January 2019; and primary analyses are projected to be completed by February 2019.
Breast Cancer Lung Metastasis
Kleef and co-workers (2018) noted that the prognosis of triple-negative breast cancer with metastases after chemotherapy remains dismal. These investigators reported the case of a 50-year old woman with first disease recurrence at the axillary lymph node and, later on, bilateral pulmonary metastases with severe shortness of breath. She received low-dose immune checkpoint blockade (LD-ICB; concurrent nivolumab and ipilimumab) weekly over 3 weeks with regional hyperthermia 3 times a week, followed by systemic fever-range hyperthermia induced by IL-2 for 5 days. The patient went into CR of her pulmonary metastases with transient WHO I-II diarrhea and skin rash. She remained alive for 27 months after the start of treatment, with recurrence of metastases as a sternal mass, and up to 3 cm pleural metastases. The authors concluded that this protocol (LD-ICB induced autoimmune T-cells further stimulated by IL-2 and hyperthermia) represents a potentially powerful therapeutic strategy that would seem deserving of evaluation in controlled clinical trials.
Candidiasis
Rodríguez-Cerdeira and colleagues (2018) stated that susceptibility to Candida spp. infection is largely determined by the status of host immunity, whether immuno-compromised/immuno-deficient or immuno-competent. Interleukin-2 is a 4-alpha-helix bundle cytokine induced by activated T cells with 2 important roles: the activation and maintenance of immune responses, and lymphocyte production and differentiation. These investigators reviewed the roles of cytokines as immune stimulators and suppressors of Candida spp. infections as an update on this continuously evolving field. They performed a comprehensive search of the Cochrane Central Register of Controlled Trials, Medline (PubMed), and Embase databases for articles published from March 2010 to March 2016 using the following search terms: interleukins, interleukin-2, Candida spp., and immunosuppression. Data from the authors’ own studies were also reviewed. They provided an overview focusing on the ability of IL-2 to induce a large panel of trafficking receptors in skin inflammation and control T helper (Th)2 cytokine production in response to contact with Candida spp. Immunocompromised patients have reduced capacity to secrete Th1-related cytokines such as IL-2. The ability to secrete the Th1-related cytokine IL-2 is low in immuno-compromised patients. This prevents an efficient Th1 immune response to Candida spp. antigens, making immuno-compromised patients more susceptible to candidal infections. The authors concluded that the present review of the literature on the role of IL-2 in host responses to Candida infection suggested that low levels of IL-2 and interferon-gamma ( IFN-γ) secretion in response to fungal pathogen-produced antigens might substantially account for the deficient cell-mediated immunity observed in patients with fungal infections. This reduction in IL-2 and IFN-γ levels might mainly be due to the decrease in Th1 cell numbers. Therefore, modification of cytokine production might be a dominant mechanism contributing to the greater susceptibility to Candida infections in patients suffering from other chronic infections. The lowered capacity to secrete IL-2, IL-17, and IFN-γ and the low production of IL-10 suggested that, in these patients, fungal antigens are incapable of promoting sufficient secretion of Th1 cytokines, instead resulting in enhanced secretion of Th2 cytokines. These researchers stated that additional studies assessing the secretion of other cytokines typical of Th1 or Th2 responses are needed to validate this potential mechanism, and would contribute to the development of new therapeutic approaches, especially for immuno-compromised patients.
Malignant Pleural Effusion
Han and associates (2018) noted that IL-2 is an important immunotherapy cytokine for various diseases including cancer. Some studies reported the safety and efficacy on cisplatin combined with IL-2 versus cisplatin alone for treating malignant pleural effusion (MPE) through thoracic injection. These investigators searched for these studies from medical electronic database. A total of 18 studies that met the inclusion criteria were recruited in this meta-analysis. Pooled OR with 95 % CI were determined by the fixed effects model of meta-analysis. The objective response rate (ORR) and disease control rate (DCR) of cisplatin plus IL-2 for controlling MPE was significantly higher than that of cisplatin alone (p < 0.001). In addition, compared with cisplatin alone, the presence of IL-2 improved the QOL of patients with MPE (p < 0.001). Although the use of IL-2 appeared to increase the probability of fever in patients (p = 0.001), it did not lead to extra AEs including myelotoxicity, nausea/vomiting and chest pain (p > 0.05). The authors concluded that the findings of this meta-analysis showed that thoracic injection of cisplatin plus low-dose IL-2 had a better benefit of ORR, DCR and QOL for controlling MPE, compared with cisplatin alone, which meant that IL-2 may be one of the options to treat MPE. Especially, except for the fever, the presence of low-dose IL-2 did not have an extra increase on the incidence of other AEs. However, these researchers stated that further randomized trials with large population are needed to provide more evidence for evaluating the efficacy of IL-2 in the treatment of MPE.
The authors stated that this study had several drawbacks. First the dosage of IL-2 was defined 1 to 3 million units in those studies; IL-2 dose showed some differences, suggesting that the IL-2 combined with cisplatin by thoracic injection for MPE treatment needs further standardization. Second, the description of randomized allocation and blinded implementation of included studies was unclear and there may be a risk of selective bias, which may affect the strength of evidence of the findings. Third, because there was no foreign literature to meet the inclusion criteria, there may be a geographical bias. Fourth, to-date, there are no multi-center and large sample studies. These researchers hope that in the future there will be more scientifically designed and rigorous RCTs of large samples to provide a reliable basis for the clinical use of IL-2 in treatment of MPE by thoracic injection.
Tuberculosis
Zhang and colleagues (2018) stated that IL-2 is a cytokine secreted by activated T cells. Studies exploring recombinant human IL-2 (rhuIL-2) as an adjunctive immunotherapeutic agent to treat tuberculosis (TB) have shown variable results; however, the true therapeutic efficacy of rhuIL-2 administration in TB patients has not been determined. These researchers carried out a systematic review to identify publications exploring the association between rhuIL-2-based immunotherapy for TB and outcomes (sputum culture conversion, sputum smear conversion, radiographic changes, and leukocyte phenotype changes) in patients with pulmonary TB published before June 8, 2018. Data were extracted and analyzed by 2 investigators independently. A total of 2,272 records were screened; 4 RCTs comprising 656 pulmonary TB patients were finally included. The rhuIL-2 treatment could significantly improve the sputum culture conversion of TB (RR, 1.18; 95 % CI: 1.03 to 1.36; I2 < 0.01; p = 0.019) after at least 3 months of anti-TB therapy and the sputum smear conversion of TB during anti-TB therapy. Treating multidrug-resistant tuberculosis (MDR-TB) with rhuIL-2 could improve the sputum culture conversion (RR, 1.28; 95 % CI: 1.05 to 1.57; I2 < 0.01; p = 0.016) and smear conversion (RR, 1.28; 95 % CI: 1.09 to 1.51; I2 < 0.01; p = 0.003) at the end of anti-TB treatment. Meanwhile, rhuIL-2-based adjunctive immunotherapy could expand the proliferation and conversion of CD4+ and natural killer (NK) cells; 3 of the included studies suggested that radiographic changes could not be improved by the use of rhuIL-2 as adjunctive immunotherapy; publication bias did not exist. The authors concluded that treating TB with rhuIL-2 could expand the proliferation and conversion of CD4+ and NK cells as well as improve the sputum culture (at 3 months and later) and smear conversion of TB. However, rhuIL-2 treatment did not enhance the radiographic changes. They stated that large scale, well-designed, multi-center clinical trials are needed in the future.
The authors stated that this study had several drawbacks. First, the patients came from China, South Africa, and Uganda. Thus, the representation and reliability of the results were poor. Second, these investigators did not evaluate some prospective observational studies that involved rhuIL-2-based adjunctive immunotherapy on TB patients. Third, the protocols of rhuIL-2 intervention (rhuIL-2 source, beginning times, delivery methods, dosages, schedules, and therapy period) of rhuIL-2 were different in each study. Fourth, many methods were used among the studies. For example, 1 study did not clearly state the randomization methods, and only 1 study was performed in a double-blind manner, while the remaining 3 were not. Finally, the diagnostic criteria of the radiographic changes were not unified. Given these limitations, more prospective RCTs with a large sample size and a strict design are needed in future studies.
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