Tisagenlecleucel (Kymriah)

Number: 0920

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses tisagenlecleucel (Kymriah) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of tisagenlecleucel (Kymriah) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of tisagenlecleucel (Kymriah), call 1-877-212-8811.

  1. Exclusions

    Aetna will not provide coverage for members with any of the following exclusions:

    1. Previous treatment course with the requested medication or another CD19-directed chimeric antigen receptor (CAR) T-cell therapy; or
    2. Inadequate and unstable kidney, liver, pulmonary and cardiac function; or
    3. Active or latent hepatitis B, active hepatitis C or any active uncontrolled infection; or
    4. Active graft versus host disease; or
    5. Active inflammatory disorder
  2. Criteria for Initial Approval

    Aetna considers tisagenlecleucel (Kymriah) medically necessary for any of the following indications:

    1. Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

      For treatment of B-cell precursor ALL in members less than 26 years of age for when all of the following criteria are met:

      1. Member has CD19 tumor expression in bone marrow or peripheral blood; and
      2. Member has at least 5% lymphoblasts in the bone marrow; and
      3. Member meets either of the following:

        1. Member has Philadelphia chromosome-negative disease that is refractory or has had two or more relapses; or
        2. Member has Philadelphia chromosome-positive disease and meets any of the following:

          1. Member has refractory disease; or
          2. Member has had two or more relapses and has failed at least two tyrosine kinase inhibitors (TKIs) (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib); or
          3. Member has relapsed disease and is TKI intolerant; or
          4. Member has experienced a relapse post-hematopoietic stem cell transplant (HSCT); and
      4. Member has a Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status greater than or equal to 50%
    2. Adult B-cell Lymphomas

      For treatment of B-cell lymphomas in members 18 years of age or older when all of the following criteria are met:

      1. Member has any of the following B-cell lymphoma subtypes:

        1. Diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma; or
        2. Follicular lymphoma; or
        3. Histologic transformation of indolent lymphomas to DLBCL; or
        4. Diffuse large B-cell lymphoma (DLBCL); or
        5. High-grade B-cell lymphomas (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified); or
        6. Human immunodeficiency virus (HIV)-related B-cell lymphomas (including HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specific); or
        7. Monomorphic post-transplant lymphoproliferative disorder (B-cell type); and
      2. The member has received prior treatment with two or more lines of systemic therapy; and
      3. The member does not have primary central nervous system lymphoma; and
      4. Member has an ECOG performance status of 0 to 2 (see Appendix).

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  3. Continuation of Therapy

    See Dosage and Administration information.

  4. Related Policies

    1. CPB 0799 - Tocilizumab (Actemra)
    2. CPB 0924 - Axicabtagene Ciloleucel (Yescarta)

Dosage and Administration

For autologous use only. For intravenous use only.

Dosage in Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

A single dose of tisagenlecleucel (Kymriah) contains 0.2 to 5.0 x 106 CAR-positive viable T cells per kg of body weight for persons 50 kg or less, or 0.1 to 2.5 x 108 CAR-positive viable T cells for persons more than 50 kg, suspended in a "patient-specific" infusion bag for intravenous infusion.

  • For persons 50 kg or less, administer 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight intravenously;
  • For persons above 50 kg, administer 0.1 to 2.5 x 108 total CAR-positive viable T cells (non-weight based) intravenously.

Dosage in Adult Relapsed or Refractory (r/r) Diffuse Large B-cell lymphoma (DLBCL) and Follicular Lymphoma (FL)

A single dose of tisagenlecleucel (Kymriah) contains 0.6 to 6.0 x 108 CAR-positive viable T cells suspended in one or more “patient-specific” infusion bag(s) for intravenous infusion. Administer 0.6 to 6.0 x 108 CAR-positive viable T cells intravenously.

Source: May 2022

Experimental and Investigational

Aetna considers tisagenlecleucel experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

  • Adult (26 years of age or older) acute lymphoblastic leukemia (ALL)
  • Acute myeloid leukemia (AML)
  • Chronic lymphocytic leukemia (CLL)
  • Hodgkin lymphoma (HL)
  • Plasma cell disorders (e.g., multiple myeloma (MM))
  • Primary central nervous system lymphoma
  • Relapsed or refractory extramedullary leukemia
  • Solid tumors (e.g., glioma, glioblastoma and neuroblastoma)
  • T-cell leukemia/lymphoma (e.g., acute T-cell leukemia, adult T-cell leukemia/lymphoma, anaplastic large-cell lymphoma, and cutaneous T cell lymphoma).

Aetna considers repeat administration of tisagenlecleucel (Kymriah) experimental and investigational because the effectiveness of this approach has not been established.


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

CPT codes covered if selection criteria are met:

0537T - 0540T Chimeric antigen receptor T-cell (CAR-T) therapy

Other CPT codes related to the CPB:

96365 - 96368 Intravenous infusion administration
96413 - 96417 Intravenous chemotherapy administration

HCPCS codes covered if selection criteria are met :

Q2042 Tisagenlecleucel, up to 600 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose

ICD-10 codes covered if selection criteria are met:

C82.00 - C82.99 Follicular lymphoma
C83.30 - C83.39 Diffuse large B-cell lymphoma
C91.00 - C91.02 Acute lymphoblastic leukemia
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)

ICD-10 codes not covered for indications listed in the CPB:

C71.0 - C71.9 Malignant neoplasm of the brain
C74.00 - C74.92 Malignant neoplasm of adrenal gland
C81.00 - C81.99 Hodgkin lymphoma
C84.A0 - C84.A9 Cutaneous T-cell lymphoma, unspecified
C84.60 - C84.79 Anaplastic large cell lymphoma, ALK-positive or negative
C90.00 - C90.02 Multiple myeloma
C90.20 - C90.22 Extramedullary plasmacytoma
C91.10 - C91.12 Chronic lymphocytic leukemia (CLL)
C91.50 - C91.52 Adult T-cell leukemia/lymphoma (HTLV-1 associated)
C91.60 - C91.62 Prolymphocytic leukemia of T-cell type
C92.00 - C92.02 Acute myeloblastic leukemia


U.S. Food and Drug Administration (FDA)-Approved Indications

  • Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

    Kymriah is indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

  • Adult Relapsed or Refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL)

    Adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

  • Adult Relapsed or Refractory (r/r) Follicular Lymphoma (FL)

    Adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy.

Limitations of Use:

Kymriah is not indicated for treatment of patients with primary central nervous system lymphoma.

Compendial Uses

  • Pediatric B-cell ALL first relapse post hematopoietic stem cell transplant (HSCT)
  • Histologic transformation of indolent lymphomas to DLBCL
  • Human immunodeficiency virus (HIV)-related B-cell lymphomas (including HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specific)
  • Monomorphic post-transplant lymphoproliferative disorder (B-cell type)

Tisagenlecleucel is available as Kymriah (Novartis Pharmaceuticals Corporation, 2020) and is a CD19-directed genetically modified autologous T cell immunotherapy which consists of reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. Kymriah is prepared from the patient's peripheral blood mononuclear cells, which are collected via a standard leukapheresis procedure. The CAR is made up of a murine single-chain antibody fragment which recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. By binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the Kymriah cells (Novartis, 2020).

Per the prescribing information, tisagenlecleucel (Kymriah) carries the following boxed warnings:

  • Cytokine release syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred in 79% (54/68) of pediatric and young adult patients with relapsed or refractory (r/r) ALL and 74% (78/106) adult patients with r/r DLBCL receiving Kymriah, including ≥ Grade 3 in 49% of patients with r/r ALL and in 23% of patients with r/r DLBCL;
  • Neurological toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 72% (49/68) patients with r/r ALL and 58% (62/106) patients with r/r DLBCL after Kymriah treatment, including ≥ Grade 3 in 21% of patients with r/r ALL and 18% of patients with r/r DLBCL.

Tisagenlecleucel (Kymriah) carries the following additional warnings and precautions (Novartis, 2020):

  • Hypersensitivity reactions
  • Serious infections
  • Prolonged cytopenias
  • Hypogammaglobulinemia
  • Secondary malignancies
  • Effects on ability to drive and use machines.

Per the prescribing information, tisagenlecleucel (Kymriah) carries the following adverse reactions:

  • For pediatric and young adult B-cell ALL (up to 25 years of age): The most common adverse reactions (occurrence > 20%) are cytokine releasing syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, edema, cough and delirium. 
  • For adult relapsed or refractory diffuse large B-cell lymphoma: The most common adverse reactions (occurrence > 20%) are CRS, infections-pathogen unspecified, pyrexia, diarrhea, nausea, fatigue, hypotension, edema and headache.

Acute leukemia is the most common form of childhood cancer, comprising about 30 % of all childhood malignancies; and acute lymphoblastic leukemia (ALL) occurs 5 times more commonly than acute myeloid leukemia (AML).  Survival rates for ALL have improved significantly since the 1980s, with current 5-year overall survival (OS) rates estimated at greater than 85 %; and 5-year event-free survival (EFS) rates are greater than 93 % for low-risk groups (Horton and Steuber, 2020).  However, relapsed and chemotherapy-refractory B-cell ALL (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children and adults.  Development of new molecularly targeted treatment strategies for patients with high-risk B-ALL is thus a major pre-clinical and clinical priority.  Adoptive cellular therapy with patient-derived chimeric antigen receptor (CAR) modified T cells targeting CD19 is one immunotherapeutic modality that has recently demonstrated remarkable efficacy in re-inducing remission in patients with relapsed B-ALL. 

Luskin and DeAngelo (2017) noted that over 50 % of patients diagnosed with B-cell ALL develop relapsed or refractory disease (r/r B-ALL).  Traditional chemotherapy salvage is inadequate, and new therapies are needed; CAR T cell therapy is a novel, immunologic approach where T cells are genetically engineered to express a CAR conferring specificity against a target cell surface antigen, most commonly the pan-B-cell marker CD19.  After infusion, CAR T cells expand and persist, allowing ongoing tumor surveillance.  Several anti-CD19-CAR T cell constructs have induced high response rates in heavily pre-treated populations, although durability of response varied.  Moreover, severe toxicity (cytokine release syndrome [CRS] and neurotoxicity) is the primary hurdle to broad implementation of CAR T cell therapy.  Tisagenlecleucel is a CAR T cell therapy for children and young adults with r/r B-ALL.

B-Cell Precursor Acute Lymphoblastic Leukemia (B-ALL)

Lee and colleagues (2015) stated that CD19-CAR T cell therapy had shown activity in case series of patients with ALL, chronic lymphocytic leukemia (CLL), and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported.  In a phase I, dose-escalation, clinical trial, these researchers defined feasibility, toxicity, maximum tolerated dose (MTD), response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells.  These investigators enrolled children and young adults (aged 1 to 30 years) with r/r B-ALL or non-Hodgkin lymphoma (NHL).  Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signaling domains.  All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells.  Using a standard 3 + 3 design to establish the MTD, patients received either 1 × 10(6) CAR-transduced T cells/kg (dose 1), 3 × 10(6) CAR-transduced T cells/kg (dose 2), or the entire CAR T cell product if sufficient numbers of cells to meet the assigned dose were not generated.  After the dose-escalation phase, an expansion cohort was treated at the MTD.  Between July 2, 2012 and June 20, 2014, a total of 21 patients (including 8 who had previously undergone allogeneic hematopoietic stem-cell transplantation [allo-HSCT]) were enrolled and infused with CD19-CAR T cells; 19 received the prescribed dose of CD19-CAR T cells, but the assigned dose concentration could not be generated for 2 patients (90 % feasible).  All enrolled patients were evaluated for response.  The MTD was defined as 1 × 10(6) CD19-CAR T cells/kg.  All toxicities were fully reversible, with the most severe being grade-4 CRS that occurred in 3 (14 %) of 21 patients (95 % confidence interval [CI]: 3.0 to 36.3).  The most common non-hematological grade-3 adverse events (AEs) were fever (9 [43 %] of 21 patients), hypokalemia (9 [43 %] of 21 patients), fever and neutropenia (8 [38 %] of 21 patients), and CRS (3 [14 %] of 21 patients).  The authors concluded that CD19-CAR T cell therapy was feasible, safe, and mediated potent anti-leukemic activity in children and young adults with r/r B-ALL.  All toxicities were reversible and prolonged B-cell aplasia did not occur.

Tasian and Gardner (2015) noted that researchers at several major institutions were conducting phase I clinical trials in children and/or adults with r/r B-ALL to (i) assess the safety and (ii) identify the MTD of each group's CD19 CAR T-cell product.  All groups have reported major clinical toxicities associated with CD19 CAR T cell treatment, including CRS and macrophage activation syndrome, neurologic dysfunction and aplasia of normal B lymphocytes, while CD19-CAR T cells persist in-vivo.  Toxicities have generally been transient or manageable with supportive care measures.  Some patients with life-threatening CD19-CAR T cell induced sequelae have received anti-cytokine receptor antibody treatment to diminish CRS symptoms and/or corticosteroids to terminate CAR T cell proliferation; 67 to 90 % of children and adults with B-ALL treated with CD19-CAR T cells in these trials have achieved morphologic leukemia remission with many patients also in molecular remission.  The duration of CD19-CAR T cell persistence in-vivo has varied appreciably among treated patients and likely reflected differences in the CD19-CAR constructs utilized at each institution.  The authors noted that CD19-positive and CD19-negative B-ALL relapses after CD19-CAR T cell treatment have occurred in some patients; phase II clinical trials to evaluate the effectiveness of CD19-CAR T cell immunotherapy in larger cohorts of patients with chemotherapy r/r B-ALL were ongoing or planned.

Tang and associates (2016) stated that there is no curative treatment available for patients with chemotherapy r/r B-ALL.  Although CD19-targeting 2nd-generation (2nd-G) CAR-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signaling domains endowed CAR-T cells with different and complementary functional properties.  Pre-clinical results have shown that 3rd-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signaling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain.  In a proposed, non-randomized, open-label, phase I clinical trial, these researchers examined the safety and effectiveness of 3rd-G CAR-T cells in adults with r/r B-ALL.  Before receiving lympho-depleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leuka-pheresed, and the T cells will be purified, activated, transduced and expanded ex-vivo.  On day 6 in the protocol, a single-dose of 1 million CAR-T cells/kg will be administrated intravenously.  The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2 years after CAR-T infusion using flow cytometry, real-time quantitative PCR (rt-qPCR) and cytometric bead array, respectively.  Moreover, several predictive plasma cytokines including interferon gamma (IF-γ), interleukin (IL)-6, IL-8, soluble IL (sIL)-2R-α, soluble glycoprotein (sgp) 130, sIL-6R, monocyte chemoattractant protein (MCP1), macrophage inflammatory protein (MIP1)-α, MIP1-β and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe CRS, will be used to forecast CRS to allow doing earlier intervention, and CRS will be managed based on a revised CRS grading system.  In addition, patients with grade-3 or grade-4 neuro-toxicities or persistent B-cell aplasia will be treated with dexamethasone (10 mg intravenously every 6 hours) or IgG, respectively.  Descriptive and analytical analyses will be performed.  The results of the proposed study will be reported, through peer-reviewed journals, conference presentations and an internal organizational report.

Callahan and co-workers (2017) stated that immunotherapy provides a promising therapeutic option for children and adolescents with r/r B-ALL.  These investigators presented a hospital's experience with providing CAR T cell therapy, followed by a detailed discussion of the trajectory of treatment provided for pediatric patients and their families.  Of 59 patients who were treated with CAR T cell therapy at the authors' institution, 93 % had a complete response (CR) at day 28.  The 12-month relapse-free survival rate was 55 %.  The authors stated that a multi-disciplinary team of skilled clinicians is recommended to support patient and family needs throughout screening, treatment, and follow-up while coordinating care with the referring oncologist.

Pan and co-workers (2017) treated 42 primary r/r B-ALL and 9 refractory minimal residual disease by flow cytometry (FCM-MRD+) B-ALL patients with optimized 2nd-G CD19-directed CAR T cells. The CAR T cell infusion dosages initially ranged from 0.05 to 14 × 105/kg and eventually settled at 1 × 105/kg for the most recent 20 cases; 36/40 (90 %) evaluated r/r patients achieved CR or CR with incomplete count recovery (CRi), and 9/9 (100 %) FCM-MRD+ patients achieved MRD-.  All of the most recent 20 patients achieved CR/CRi.  Most cases only experienced mild-to-moderate CRS; 8/51 cases had seizures that were relieved by early intervention; 23 of 27 CR/CRi patients bridged to allo-HCT remained in MRD- with a median follow-up of 206 (45 to 27) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed.  The authors concluded that these findings indicated that a low CAR-T cell dosage of 1 × 105/kg, was safe and effective in treating r/r B-ALL, and subsequent allo-HCT could further reduce the relapse rate.

On August 30, 2017, the Food and Drug Administration (FDA) approved Kymriah (tisagenlecleucel) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.  The safety and effectiveness of Kymriah were demonstrated in 1 multi-center clinical trial of 63 pediatric and young adult patients with r/r B-ALL.  The overall remission rate within 3 months of treatment was 83 %.  To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.  The most common adverse reactions (incidence greater than 20 %) are CRS, hypo-gammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium.

Per the Prescribing Information, the effectiveness of Kymriah in pediatric and young adults with r/r B-ALL was evaluated in an open-label, multi-center single-arm trial (Study 1).  In total, 107 patients were screened, 88 were enrolled, 68 were treated, and 63 were evaluable for efficacy; 9 % of the enrolled subjects did not receive the product due to manufacturing failure.  The 63 evaluable patients included 35 males and 28 females of median age 12 years (range of 3 to 23 years); 73 % of patients were white, 10 % were Asian, and 17 % were of other races; 6 (10 %) had primary refractory disease, 30 (48 %) had 1 prior SCT, 5 patients (8 %) had 2 SCTs.  Treatment consisted of lympho-depleting chemotherapy (fludarabine 30 mg/m2 daily for 4 days and cyclophosphamide 500 mg/m2 daily for 2 days) followed by a single-dose of Kymriah.  Of the 22 patients who had a white blood cell (WBC) count of less than 1,000/μL, 20 received lympho-depleting chemotherapy prior to Kymriah while 2 received Kymriah infusion without lympho-depleting chemotherapy; 53 patients received bridging chemotherapy between time of enrollment and lympho-depleting chemotherapy.  The effectiveness of Kymriah was established on the basis of CR within 3 months after infusion, the duration of CR, and proportion of patients with CR and minimal residual disease (MRD) of less than 0.01 % by flow cytometry (MRD-negative).  Among the 63 infused patients, 52 (83 %) achieved CR/CRi, all of which were MRD-negative.  With a median follow-up of 4.8 months from response, the median duration of CR/CRi was not reached (range of 1.2 to 14.1+ months).  Median time to onset of CR/CRi was 29 days with onset of CR/CRi between 26 and 31 days for 50/52 (96 %) responders.  The SCT rate among those who achieved CR/CRi was 12 % (6/52).

Tisagenlecleucel is also being studied for the treatment of various malignancies including hematologic diseases, plasma cell disorders, solid tumors and T-cell leukemias/lymphomas; however, its effectiveness for these indications has not been established.

Acute Myeloid Leukemia (AML)

Tashiro and colleagues (2017) noted that the successful immunotherapy of acute myeloid leukemia (AML) has been hampered because most potential antigenic targets are shared with normal hematopoietic stem cells (HSCs), increasing the risk of sustained and severe hematopoietic toxicity following treatment.  C-type lectin-like molecule 1 (CLL-1) is a membrane glycoprotein expressed by greater than 80 % of AML, but is absent on normal HSCs.  These researchers described the development and evaluation of CLL-1-specific CAR T cells (CLL-1.CAR-Ts) and demonstrated their specific activity against CLL-1+ AML cell lines as well as primary AML patient samples in-vitro.  CLL-1.CAR-Ts selectively reduced leukemic colony formation in primary AML patient peripheral blood mononuclear cells compared to control T cells.  In a human xenograft mouse model, CLL-1.CAR-Ts mediated anti-leukemic activity against disseminated AML and significantly extended survival.  By contrast, the colony formation of normal progenitor cells remained intact following CLL-1.CAR-T treatment.  Although CLL-1.CAR-Ts are cytotoxic to mature normal myeloid cells, the selective sparing of normal hematopoietic progenitor cells should allow full myeloid recovery once CLL-1.CAR-T activity terminates.  To enable elective ablation of the CAR-T, the authors therefore introduced the inducible caspase-9 suicide gene system and showed that exposure to the activating drug rapidly induced a controlled decrease of unwanted CLL-1.CAR-T activity against mature normal myeloid cells.  These preliminary findings need to be further investigated in clinical trials.

Central Nervous System Lymphoma

Wu et al (2021) stated that the safety and effectiveness of chimeric antigen receptor T (CAR-T) cell therapy in the treatment of NHL has already been demonstrated. However, patients with a history of/active secondary central nervous system (CNS) lymphoma were excluded from the licensing trials conducted on 2 widely used CAR-T cell products, axicabtagene ciloleucel (Axi-cel) and tisagenlecleucel (Tisa-cel). In a systematic review, these investigators examined if secondary CNS lymphoma patients would derive a benefit from Axi-cel or Tisa-cel therapy, while maintaining controllable safety. Two reviewers searched PubMed, Embase, Web of Science, and Cochrane library independently to identify all records associated with Axi-cel and Tisa-cel published before February 15, 2021. Studies that included secondary CNS lymphoma patients treated with Axi-cel and Tisa-cel and reported or could be inferred safety and effectiveness endpoints of secondary CNS lymphoma patients were included. A tool designed specifically to evaluate the risk of bias in case series and reports and the ROBINS-I tool applied for cohort studies were used. A total of 10 studies involving 44 patients were included. Of these, 7 were case reports or series. The other 3 reports were cohort studies involving 25 patients. Current evidence indicated that secondary CNS lymphoma patients could achieve long-term remission following Axi-cel and Tisa-cel treatment. Compared with the non-CNS cohort, however, PFS and OS tended to be shorter. This was possibly due to the relatively small size of the CNS cohort. The incidence and grades of adverse effects in secondary CNS lymphoma patients resembled those in the non-CNS cohort. No incidences of CAR-T cell-related deaths were reported. Nevertheless, the small sample size introduced a high risk of bias and prevented the identification of specific patients who could benefit more from CAR-T cell therapy. The authors concluded that secondary CNS lymphoma patients appeared to benefit from both Axi-cel and Tisa-cel treatment, with controllable risks; therefore, CAR-T cell therapy has potential as a candidate treatment for lymphoma patients with CNS involvement. Moreover, these researchers stated that further prospective studies with larger samples and longer follow-up periods are needed and recommended.

Frigault et al (2022) noted that CD19-directed CAR-T products have gained FDA approval for systemic large B-cell lymphoma. Because of concerns regarding potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary CNS lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. These researchers carried out a phase-I/II clinical trial of tisagenlecleucel in highly refractory patients with PCNSL and significant unmet medical need. They presented findings of 12 relapsed patients with PCNSL who were treated with tisagenlecleucel and followed for a median time of 12.2 months (range of 3.64 to 23.5). Grade-1 CRS was observed in 7/12 patients (58.3 %), low-grade ICANS in 5/12 (41.6 %) patients, and only 1 patient experienced grade-3 ICANS; 7 of 12 patients (58.3 %) demonstrated response, including a CR in 6/12 patients (50 %). There were no treatment-related deaths; 3 patients had ongoing CR at data cut-off. Tisagenlecleucel expanded in the peripheral blood and trafficked to the CNS. Exploratory analysis identified T-cell, CAR T, and macrophage gene signatures in cerebrospinal fluid following infusion when compared with baseline. Overall, tisagenlecleucel was well-tolerated and resulted in a sustained remission in 3/7 (42.9 %) of initial responders. The authors concluded that the findings of this study suggested that tisagenlecleucel was safe and effective in this highly refractory patient population.

Yi et al (2022) noted that CAR T-cell therapy has significantly improved the outcomes of patients with r/r B-NHL; however, most clinical trials excluded patients with CNS involvement due to uncertain safety and effectiveness.  On January 1, 2022, these investigators searched PubMed to identify all published literature associated with current commercial CAR T-cell therapies for B-NHL, including tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), and lisocabtagene maraleucel (liso-cel).  Studies that involved patients with either primary or secondary CNS lymphoma, and evaluated response rate, AEs, or survival were included and summarized.  These researchers summarized the findings of 11 studies qualified for their inclusion criteria, reporting 58 lymphoma patients with CNS Involvement with 44 evaluable for clinical response (CR), 25 for immune effector cell-associated neurotoxicity syndrome (ICANS) and 48 for CRS.  Objective response was achieved in 62 % (16/26) of patients, and CR was achieved in 52 % (23/44) of patients; 44 % (11/25) developed ICANS, and 35 % (17/48) developed severe ICANS (grade-III or higher).  CRS was reported in 63 % (15/24) of patients, while severe CRS (grade-III or higher) was reported in 7 % (3/42) of patients.  The authors concluded that CAR T-cell therapy may benefit patients with CNS lymphoma with promising response rates and acceptable AE.  Moreover, these researchers stated that definite conclusions cannot be made until data with a larger sample size are available.

Zhang et al (2022) stated that encouraging response has been achieved in r/r B-cell lymphoma treated by CAR-T therapy.  The safety and effectiveness of CAR-T therapy in CNS lymphoma (CNSL) are still elusive.  In a retrospective study, these researchers analyzed 15 patients with r/r secondary CNSL receiving CD19-specific CAR-T cell-based therapy.  Subjects were infused with CD19, CD19/CD20 or CD19/CD22 CAR-T cells following a conditioning regimen of cyclophosphamide and fludarabine.  The ORR was 73.3 % (11/15), including 9 (60 %) with CR and 2 (13.3 %) with PR.  During a median follow-up of 12 months, the median PFS was 4 months, and the median OS was 9 months.  Of 12 patients with systemic tumor infiltration, 7 (58.3 %) achieved CR in CNS, and 5 (41.7 %) achieved CR both systemically and in CNS.  Median DOR for CNS and systemic disease were 8 and 4 months, respectively.  At the end point of observation, of the 7 patients achieved CNS disease CR, 1 was still alive with sustained CR of CNS disease and systemic disease.  The other 6 died of systemic progression.  Of the 15 patients, 11 (73.3 %) experienced grades I to II CRS, and no patient had grades III to IV CRS.  ICANS occurred in 3 (20 %) patients, including 1 (6.6 %) with grade-IV ICANS.  All the CRS or ICANS were manageable.  The authors concluded that the CD19-specific CAR-T cell-based therapy appeared to be a promising therapeutic approach in secondary CNSL, based on its anti-tumor effects and an acceptable side effect profile, meanwhile more strategies are needed to maintain the response.  Moreover, these researchers stated that their findings were limited by the retrospective nature of the analyses, small number of cases (n = 15) and non-uniform CAR-T cell types.  These investigators plan to carry out a prospective, clinical study to further clarify the safety and effectiveness of CAR T-cell therapy for secondary CNSL, as well as the selection and application timing of subsequent maintenance therapy.

Chronic Lymphocytic Leukemia (CLL)

Singh and colleagues (2016) stated that adoptive transfer of autologous T cells engineered to express a CAR represents a powerful targeted immunotherapy that has shown great promise in some of the most refractory leukemia.  CAR-modified T cells directed against CD19 have led the way, setting a high standard with remission rates as high as 90 % in clinical trials for r/r B-ALL.  Yet, the first demonstration of effectiveness was in CLL, in which CD19-targeted CAR T cells eradicated bulky, highly refractory disease.  Despite early encouraging results, clinical trials in CLL have yielded lower response rates, revealing disease-specific differences in response in this form of immunotherapy.  Ongoing research focused on identifying and overcoming these limitations, as well as improving response rates.  Beyond the induction of remission, the transformative impact of engineered T cell therapy lies in its potential for long-term disease control.  As might be expected with a highly effective therapy using a single mechanism of action, escape pathways have emerged.  The authors stated that combinatorial approaches are needed to anticipate and prevent this mode of relapse.  In addition, toxicity management is critical in ensuring the safety of this exciting cancer immunotherapy.

Diffuse Large B Cell Lymphoma (DLBCL)

Kochenderfer and associates (2017) noted that T cells expressing anti-CD19 CARs can induce complete remissions of diffuse large B cell lymphoma (DLBCL); however, the long-term durability of these remissions is unknown.  These researchers administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL; 5 of the 7 evaluable patients obtained CRs; 4 of the 5 CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to-date, none of these 4 cases of lymphomas had relapsed.  More importantly, CRs continued after recovery of non-malignant polyclonal B cells in 3 of the 4 patients with long-term CRs.  In these 3 patients, recovery of CD19+ polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these 3 patients remained in CR at the last follow-up.  Non-malignant CD19+ B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations.  Patients had a low incidence of severe infections despite long periods of B cell depletion and hypo-gammaglobulinemia.  Only 1 hospitalization for an infection occurred among the 4 patients with long-term CRs.  These preliminary findings need to be further investigated.

Locke and colleagues (2017) stated that outcomes for patients with refractory DLBCL are poor.  In the multi-center ZUMA-1 phase I clinical trial, these investigators evaluated KTE-C19, an autologous CD3ζ/CD28-based CAR T cell therapy, in patients with refractory DLBCL.  Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days followed by KTE-C19 at a target dose of 2 × 106 CAR T cells/kg.  The incidence of dose-limiting toxicity (DLT) was the primary end-point.  A total of 7 patients were treated with KTE-C19 and 1 patient experienced a DLT of grade-4 CRS and neurotoxicity.  Grade-3 or higher CRS and neurotoxicity were observed in 14 % (n = 1/7) and 57 % (n = 4/7) of patients, respectively.  All other KTE-C19-related grade-3 or higher events resolved within 1 month.  The overall response rate (ORR) was 71 % (n = 5/7) and CR rate was 57 % (n = 4/7); 3 patients have ongoing CR (all at 12+ months).  The authors concluded that CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR.  They stated that this regimen of KTE-C19 was safe for further investigation in phase II clinical trials in patients with refractory DLBCL.

In a multi-center, phase-II clinical trial, Neelapu and colleagues (2017) enrolled 111 patients with DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy.  Patients received a target dose of 2 × 106 anti-CD19 CAR T cells per kg of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine.  The primary end-point was the rate of objective response (calculated as the combined rates of CR and partial response [PR]); secondary end-points included OS, safety, and biomarker assessments.  Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99 %) and administered to 101 (91 %).  The ORR was 82 %, and the CR rate was 54%.With a median follow-up of 15.4 months, 42 % of the patients continued to have a response, with 40 % continuing to have a CR.  The overall rate of survival at 18 months was 52 %.  The most common AEs of grade 3 or higher during treatment were neutropenia (in 78 % of the patients), anemia (in 43 %), and thrombocytopenia (in 38 %).  Grade 3 or higher CRS and neurologic events occurred in 13 % and 28 % of the patients, respectively; 3  of the patients died during treatment.  Higher CAR T-cell levels in blood were associated with response.  The authors concluded that in this multi-center study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the CRS, and neurologic events.

Schuster and associates (2017) noted that patients with DLBCL or follicular lymphoma (FL) that is refractory to or that relapses after immuno-chemotherapy and transplantation have a poor prognosis.  High response rates have been reported with the use of T cells modified by CAR that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited.  These researchers used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with DLBCL or FL that had relapsed or was refractory to previous treatments.  Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in-vivo, and immune recovery.  A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64 %; 95 % CI: 44 to 81).  Complete remission occurred in 6 of 14 patients with DLBCL (43 %; 95 % CI: 18 to 71) and 10 of 14 patients with FL (71 %; 95 % CI: 42 to 92).  CTL019 cells proliferated in-vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response.  Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86 % of patients with DLBCL who had a response (95 % CI: 33 to 98) and 89 % of patients with FL who had a response (95 % CI: 43 to 98) had maintained the response.  Severe CRS occurred in 5 patients (18 %).  Serious encephalopathy occurred in 3 patients (11 %); 2 cases were self-limiting and 1 case was fatal.  All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median of 29.3 months) after induction, with a sustained re-appearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients, and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later.  The authors concluded that CTL019 cells can be effective in the treatment of relapsed or refractory DLBCL and FL.  High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients.  Transient encephalopathy developed in about 1 in 3 patients and severe CRS developed in 1 of 5 patients.

On May 1, 2018, the FDA approved Kymriah (tisagenlecleucel) suspension for intravenous infusion for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy including DLBCL, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (Novartis, 2018).  Kymriah is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma.  

Hematological Malignancies

Pasqui et al (2022) stated that hematological malignancies represent defying clinical conditions, with high levels of morbidity and mortality, especially considering patients who manifest multiple refractory diseases.  Recently, (CAR-T cell therapy has emerged as a potential therapeutic option for r/r B cell malignancies, which have motivated the FDA approval of a series of products based on this technique.  In a systematic review, these investigators examined the safety and effectiveness of CAR-T cell therapy for patients with hematological malignancies.  They carried out a comprehensive literature search in the electronic databases (CENTRAL, Embase, LILACS, and Medline), clinical trials register platforms (Clinicaltrials.gov and WHO-ICTRP), and grey literature (OpenGrey).  The Cochrane Handbook for Reviews of Interventions was used for developing the review and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for manuscript reporting.  After the selection process, a total of 7 RCTs were included, 3 of which with available outcome results.  The available results were from studies evaluating axicabtagene, lisocabtagene, and tisagenlecleucel for patients with B-cell lymphoma, and the certainty of evidence ranged from very low-to-low for survival and progression-related outcome and for safety outcomes.  Furthermore, 4 RCTs comparing CAR-T cell therapy to the standard treatment for various types of r/r B-NHL and MM included in this systematic review still did not have available outcome data.  The results of this review may be used to guide clinical practice but evidence concerning the safety and effectiveness of CAR-T Cell therapy for hematological malignancies is still immature to recommend its application outside of clinical trials or compassionate use context for advanced and terminal cases.  It is expected the results of the referred comparative studies will provide further elements to subsidize the broader application of this immunotherapy.

Hodgkin Lymphoma (HL)

Ramos and associates (2017) stated that targeting CD30 with monoclonal antibodies in anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) has had profound clinical success.  However, adverse events (AEs), mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients.  Targeting CD30 with T cells expressing a CD30-specific CAR may reduce the side effects and enhance anti-tumor activity.  These researchers carried out a phase I, dose escalation, clinical trial in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30.CAR-Ts) encoding the CD28 co-stimulatory endodomain; 3 dose levels, from 0.2 × 108 to 2 × 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen.  All other therapy for malignancy was discontinued at least 4 weeks before CD30.CAR-T infusion; 7 patients had previously experienced disease progression while being treated with brentuximab.  No toxicities attributable to CD30.CAR-Ts were observed.  Of 7 patients with relapsed HL, 1 entered CR lasting more than 2.5 years after the 2nd infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease (SD).  Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the 4th infusion of CD30.CAR-Ts.  CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks.  Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity.  The authors concluded that CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is needed.

Infant Acute Lymphoblastic Leukemia

Moskop et al (2022) noted that infants with B-ALL have poor outcomes due to chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, an FDA-approved agent for the treatment of R/R B-ALL in patients less than or equal to 25 years; however, the safety and effectiveness of this therapy in young patients is largely unknown since children of less than 3 years of age were excluded from licensing studies. These investigators retrospectively examined data from the Pediatric Real-World CAR Consortium to examine outcomes of patients with infant B-ALL who received tisagenlecleucel between 2017 and 2020 (n = 14); 64 % of patients (n = 9) achieved MRD-negative remission post-CART and 50 % of patients remained in remission at last follow-up. All patients with high disease burden at time of CART infusion (greater than M1 marrow) were refractory to this therapy (n = 5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing greater than grade-3 CRS. No neurotoxicity was reported. This was the largest report of tisagenlecleucel use in infant B-ALL and showed that this therapy was safe and could be effective in this population. These researchers stated that incorporation of this novel immunotherapy into the treatment of infant B-ALL may offer a promising therapy for a highly aggressive leukemia.

Non-Hodgkin Lymphoma (NHL)

Wang and co-workers (2016) stated that myeloablative autologous HSCT (auto-HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high.  In phase I clinical trials designed to improve long-term remission rates, these researchers administered adoptive T-cell immunotherapy after auto-HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific CARs.  These investigators presented results from 2 safety/feasibility studies (NHL1 and NHL2) examining different T cell populations and CAR constructs.  Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 10(6) in a single infusion.  In NHL1, 8 patients safely received T cell products engineered from enriched CD8(+) TCM subsets, expressing a 1st-G CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ); 4 of 8 patients (50 %; 95 % CI: 16 to 84 %) were progression-free at both 1 and 2 years.  In NHL2, 8 patients safely received T cell products engineered from enriched CD4(+) and CD8(+) TCM subsets and expressing a 2nd-G CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ); 6 of 8 patients (75 %; 95 % CI: 35 to 97 %) were progression-free at 1 year.  The CD4(+)/CD8(+) TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was 28 days or less, similar to that observed by others using CD28 CARs.  Neither CRS nor delayed hematopoietic engraftment was observed in either trial.  Based on the findings in these sequential phase I trials, the authors concluded that TCM-derived CD19CAR T-cell therapy is feasible and safe, and did not increase toxicity or delay hematopoietic engraftment of high-risk NHL patients undergoing auto-HSCT.  Neither trial escalated to MTD, as these researchers opted to implement CAR and manufacturing improvements, offering patients the most promising protocols available at the time.  These investigators continued long-term follow-up of these patients to evaluate impact on auto-HSCT outcomes.  Analysis of patient samples from these trials along with concurrent pre-clinical experiments has allowed these researchers to further refine the CAR vectors and manufacturing processes.  They stated that the next trial in this series of clinical studies was underway, with the goal of extending the duration and potency of anti-tumor immunity in the setting of immune reconstitution following autologous-HSCT (auto-HSCT).

Leslie and colleagues (2017) noted that due to recent advancements in the understanding of the molecular pathogenesis of B-cell malignancies, there has been an explosion of innovative agents in development.  These investigators summarized novel therapies with activity in indolent NHL (iNHL) targeting surface antigens, signaling pathways, and the tumor microenvironment.  They performed a literature search to identify pre-clinical data and clinical trials focused on the use of targeted therapies in iNHL subtypes including follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma/Waldenstrm macroglobulinemia.  Classes reviewed include monoclonal antibodies, antibody-drug conjugates, immunomodulatory agents, B-cell receptor pathway inhibitors, Bcl-2 inhibitors, checkpoint inhibitors, chromatin and epigenetic modulating agents, and CAR T cell therapy.  The authors provided opinions regarding strategies to address the prioritization of novel agents entering clinical development, the determination of rational combination therapy, the development of novel end-points to expedite clinical development, and the movement towards novel consolidative approaches with immunotherapy  and cellular therapy in an attempt to provide curative therapeutic options.

Plasma Cell Disorders (e.g., Multiple Myeloma (MM))

Dhodapkar and associates (2017) stated that multiple myeloma (MM) is a plasma cell malignancy characterized by the growth of tumor cells in the BM.  Properties of the tumor microenvironment provide both potential tumor-promoting and tumor-restricting properties.  Targeting underlying immune triggers for evolution of tumors as well as direct attack of malignant plasma cells is an emerging focus of therapy for MM.  The monoclonal antibodies daratumumab and elotuzumab, which target the plasma cell surface proteins CD38 and SLAMF7/CS1, respectively, particularly when used in combination with immunomodulatory agents and proteasome inhibitors, have resulted in high response rates and improved survival for patients with relapsed and refractory MM (r/r MM).  A number of other monoclonal antibodies are in various stages of clinical development, including those targeting MM cell surface antigens, the BM microenvironment, and immune effector T cells such as anti-programmed cell death protein 1 antibodies.  Bi-specific preparations seek to simultaneously target MM cells and activate endogenous T cells to enhance efficacy.  Cellular immunotherapy seeks to overcome the limitations of the endogenous anti-myeloma immune response through adoptive transfer of immune effector cells with MM specificity.  Allogeneic donor lymphocyte infusion can be effective but can cause graft-versus-host disease (GVGD).  The most promising approach appears to be genetically modified cellular therapy, in which T cells are given novel antigen specificity through expression of transgenic T-cell receptors (TCRs) or CARs.  CAR T cells against several different targets are under investigation in MM.  Infusion of CD19-targeted CAR T cells following salvage auto-SCT was safe and extended remission duration in a subset of patients with r/r MM.  CAR T cells targeting B-cell maturation antigen (BCMA) appeared most promising, with dramatic remissions seen in patients with highly refractory disease in 3 ongoing trials.  Responses were associated with degree of CAR T cell expansion/persistence and often toxicity, including CRS and neurotoxicity.  The authors noted that ongoing and future studies are examining correlates of response, ways to mitigate toxicity, and "universal" CAR T cells.

Chung (2017) noted that MM is a B-cell malignancy characterized by un-regulated growth of plasma cells in the BM.  The therapeutic paradigm for MM underwent significant changes in the past 10 years, with an improved understanding of the pathogenesis of the disease and the development of therapeutic agents that target not only the tumor cells but also their microenvironment.  Despite these improvements, the prognosis of patients with r/r MM remains poor.  Accordingly, a need exists for new therapeutic avenues that can overcome resistance to current therapies and improve survival outcomes.  In addition, MM is associated with progressive immune dysregulation, with defects in T cell immunity, natural killer cell function, and the antigen-presenting capacity of dendritic cells, resulting in a tumor microenvironment that promotes disease tolerance and progression.  Together, the immunosuppressive microenvironment and oncogenic mutations activate signaling networks that promote MM cell survival.  Immunotherapy incorporates novel therapeutic options (e.g., monoclonal antibodies, antibody-drug conjugates, CAR T cell therapy, immune checkpoint inhibitors, bi-specific antibodies, and tumor vaccines) either alone or in combination with existing lines of therapies (e.g., immunomodulatory agents, proteasome inhibitors, and histone deacetylase inhibitors) to enhance the host anti-MM immunity within the BM microenvironment and improve clinical response.  Following the FDA’s approval of daratumumab and elotuzumab in 2015, more immunotherapeutic agents are expected to be become available as valuable therapeutic options in the near future.  The author provided a basic understanding of the role of immunotherapy in modulating the BM tumor microenvironment and its role in the treatment of MM.  Clinical efficacy and safety of recently approved therapeutic monoclonal antibodies (daratumumab, elotuzumab) were discussed, along with the therapeutic potential of emerging immunotherapies (antibody-drug conjugates, CAR T cell therapy, tumor vaccines, and immune checkpoint inhibitors).

D'Agostino and colleagues (2017) stated that the treatment landscape of MM is rapidly changing; however, despite improvement in patients' survival, it still remains a largely incurable disease.  One hallmark of MM is substantial immune dysfunction leading to an increased infection rate and the inability of immune surveillance to detect neoplastic cells.  These researchers analyzed clinical approaches to harness the immune system to overcome this defect with a focus on antibody based and adoptive cellular therapies.  Clinical trials exploring these immunotherapies to treat MM are now well underway and showed promising results.  In relapsed MM, monoclonal antibodies directed against plasma cell antigens and immune checkpoints have already shown substantial efficacy.  In parallel, trials of adoptive cellular therapy have exciting promise in MM, having induced dramatic responses in a few early study participants.  The authors concluded that immunotherapeutic approaches hold enormous potential in the field of MM and in the near future can be combined with or even replace the current standard of care (CAR T cell is one of the keywords of this review).

Mikkilineni and Kochenderfer (2017) stated that MM is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed.  T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments; CARs are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains.  T cells genetically engineered to express CARs can specifically recognize antigens.  Success of CAR-Ts against leukemia and lymphoma has encouraged development of CAR-T therapies for MM.  Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited.  B-cell maturation antigen is expressed by normal and malignant plasma cells.  CAR-Ts targeting B-cell maturation antigen have demonstrated significant anti-myeloma activity in early clinical trials.  Toxicities in these trials, including CRS, have been similar to toxicities observed in CAR-T trials for leukemia.  Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy.  MM antigens including CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain are under investigation as CAR targets.  MM is genetically and phenotypically heterogeneous, so targeting of greater than 1 antigen might often be required for effective treatment of MM with CAR-Ts.  Integration of CAR-Ts with other myeloma therapies is an important area of future research.  The authors concluded that CAR-T therapies for MM are at an early stage of development, but have great promise to improve MM treatment.

Relapsed or Refractory Extramedullary Leukemia

Rubinstein and colleagues (2020) noted that autologous CD19-directed CAR-T therapy is an approved and effective treatment for the management of patients with refractory and multiply relapsed B-ALL. Experience using this therapy in pediatric patients with extra-medullary (EM) disease is limited, in part because these patients have frequently been excluded from clinical trials owing to concerns for an increased risk of immune effector cell-associated neurotoxicity syndrome (ICANS). These researchers infused 7 patients with refractory or multiply relapsed B-ALL who presented with isolated EM relapse with tisagenlecleucel; 6 patients had isolated CNS leukemia, and 1 patient had an isolated testicular relapse. An initial CR was observed in all patients, with 5 patients remaining in CAR-T-induced remission at a median of 18 months from the 1st infusion. Reversible ICANS was observed in 1 patient with CNS leukemia. Durable B cell aplasia occurred in 3 patients, with a median time to B cell recovery of 6.5 months in the remaining patients. The authors concluded that these data suggested that CAR-T therapy has promising safety and efficacy in the treatment of patients with EM leukemia, although definitive conclusions are limited by the small size of the cohort and limited follow-up period. These researchers stated that prospective, large-scale studies in patients with isolated EM relapses would be ideal to more accurately delineate the long-term clinical effectiveness of this approach and EFS without subsequent therapy along with the incidence of f immune effector cell associated neurotoxicity syndrome (ICANS) and duration of B-cell aplasia; however due to the low incidence of isolated EM relapse this is not feasible. These investigators proposed the use of a national registry of such cases in order to collect these important data.

Fabrizio et al (2022) stated that CAR-T cells have transformed the therapeutic options for r/r B-cell ALL. Data for CAR-T therapy in EM involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 U.S. institutions. Response (CR) rate, OS, relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both CNS3 and non-CNS EM) were compared with bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes were reported on 55 patients with EM disease before CAR-T therapy (CNS3, n = 40; non-CNS EM, n = 15). The median age at infusion in the CNS cohort was 10 years (range of less than 1 to 25 years), and in the non-CNS EM cohort it was 13 years (range of 2 to 26 years). In patients with CNS disease, 88 % (35 of 40) achieved a CR versus only 66 % (10 of 15) with non-CNS EM disease. Patients with CNS disease (both with and without BM involvement) had 24-month OS outcomes comparable to those of non-CNS EM or BM only (p = 0.41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM-only patients (p = 0.92). No increased toxicity was observed with CNS or non-CNS EM disease (p = 0.3). Active CNS disease at time of infusion did not affect outcomes. Isolated CNS disease trended toward improved OS compared with combined CNS and BM (p = 0.12). The authors concluded that r/r EM disease could be effectively treated with tisagenlecleucel; toxicity, relapse, and survival rates were comparable to those of patients with BM-only disease. Outcomes for isolated CNS relapse are encouraging. These researchers stated that a prospective study is needed to examine if CAR-T therapy should be the standard of care for patients with r/r EM disease to further reduce long-term side effects of radiation and SCT. In addition to efficacy, it will be important to study biological markers that correlate with treatment response, expansion data as they relate to B-cell recovery, and toxicity in patients with EM disease. These encouraging results, especially in isolated CNS relapse, warrant further study to determine where CAR T cells can best be sequenced in relapse platforms. Further expansion of study for patients in 1st relapse may reduce potential need for cranial radiation, especially in younger patients, with possible sparing of SCT.

Relapsed or Refractory Follicular Lymphoma

On May 27, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Kymriah (tisagenlecleucel) for adult patients with relapsed or refractory follicular lymphoma (FL) after two or mor lines of systemic therapy. The FDA approval was based on response rate data from the ELARA study (FDA, 2022).

In the ELARA study, a multicenter, single-arm, open-label, phase trial, Fowler and colleagues evaluated the efficacy of Kymriah (tisagenlecleucel) that included the enrollment of 98 adult patients with relapsed or refractory follicular lymphoma after two or more treatment lines or who relapsed after autologous stem cell transplant. Ninety-seven of the 98 enrolled patients received Kymriah as a single intravenous infusion with a target dose of 0.6 to 6.0 x 108 CAR-positive viable T cells following lymphodepleting chemotherapy. The primary efficacy endpoints were overall response rate (ORR) and duration of response (DOR). Primary efficacy analysis for 90 patients reported the following: ORR of 86% (95% Confidence Interval [CI]: 77, 92) with a complete response (CR) rate of 68% (95% CI: 57, 77). The median DOR was not reached, with 75% (95% CI: 63, 84) of responders still in response at 9 months. For all 98 patients undergoing leukapheresis, the ORR was 86% (95% CI: 77, 92) with a CR rate of 67% (95% CI: 57, 76) (FDA, 2022). Additionally, the most common adverse reactions (>20%) included cytokine release syndrome, infection, fatigue, musculoskeletal pain, headache, and diarrhea.

Secondary CNS Lymphoma

Tisagenlecleucel has an acceptable safety profile and showed preliminary evidence of CNS efficacy (no authors listed, 2019).

Frigault and colleagues (2019) stated that CAR T cells targeting CD19 have emerged as a leading engineered T-cell therapy for relapsed/refractory B-cell NHL (r/r B-NHL).  The phase I/II clinical trials that led to FDA approval excluded patients with CNS involvement, due to strict eligibility criteria.  These investigators reported on their institutional experience with 8 secondary CNS lymphoma patients treated with commercial tisagenlecleucel.  No patient experienced greater than grade 1 neurotoxicity, and no patient required tocilizumab or steroids for CAR T-cell-mediated toxicities.  Biomarker analysis suggested CAR T-cell expansion, despite the absence of systemic disease, and early response assessments demonstrated activity of IV infused CAR T cells within the CNS space.

Solid Tumors

Newick and colleagues (2017) noted that the field of cancer immunotherapy has been re-energized by the application of CAR T cell therapy in cancers.  These CAR T cells are engineered to express synthetic receptors that re-direct poly-clonal T cells to surface antigens for subsequent tumor elimination.  Many CARs are designed with elements that augment T cell persistence and activity.  To-date, CAR T cells have demonstrated success in eradicating hematologic malignancies (e.g., CD19 CARs in r/r B-ALL).  However, this success has yet to be extrapolated to solid tumors, and the reasons for this are being actively investigated.  These researchers characterized some of the challenges that CAR T cells have to overcome in the solid tumor microenvironment and new approaches that are being considered to address these issues.

Wang and associates (2017) stated that CAR T cells have yielded unprecedented effectiveness in B cell malignancies, most remarkably in anti-CD19 CAR T cells for B-ALL with up to a 90 % CR rate.  However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies.  In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons.  The authors characterized some of the mechanisms for antigen loss relapse and new strategies to overcome these hurdles.  In addition, they discussed some novel CAR designs that are being considered to enhance the safety of CAR T cell therapy in solid tumors.

Mata and co-workers (2017) stated that adoptive immunotherapy with T cells expressing CARs has had limited success for solid tumors in early phase clinical trials.  These researchers reasoned that introducing into CAR T cells an inducible co-stimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T cell activation.  In the presence of CID, T cells expressing HER2-CARζ and a MyD88/CD40-based iCO molecule (HER2ζ.iCO T-cells) had superior T cell proliferation, cytokine production, and ability to sequentially kill targets in-vitro relative to HER2ζ.iCO T cells without CID and T cells expressing HER2-CAR.CD28ζ.  HER2ζ.iCO T cells with CID also significantly improved survival in-vivo in 2 xenograft models.  Repeat injections of CID were able to further increase the anti-tumor activity of HER2ζ.iCO T cells in-vivo.  The authors concluded that expressing MyD88/CD40-based iCO molecules in CAR T cells has the potential to improve the effectiveness of CAR T cell therapy for solid tumors.

Jin and associates (2018) stated that cancer immunotherapy represents a promising treatment approach for malignant-gliomas, but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment.  These researchers identified CD70 as a novel immunosuppressive ligand and glioma target.  Normal tissues derived from 52 different organs, and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression.  The association between CD70 and patients' OS, and its impact on T cell death was also evaluated.  Human and mouse CD70-specific CARs were tested respectively against human primary GBMs and murine glioma lines.  The anti-tumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models.  CD70 was not detected in peripheral and brain normal tissues, but constitutively over-expressed by IDH-wildtype primary LGGs and GBMs in mesenchymal subgroup and recurrent tumors.  CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T cell-death.  To explore potential for therapeutic targeting of this newly-identified immunosuppressive axis in GBM tumors, these investigators demonstrated that both human and mouse CD70-specific CAR T cells recognized primary CD70+ GBM tumors in-vitro and mediated the regression of established GBM in xenograft and syngeneic models without illicit effect.  The authors concluded that the findings of this study identified a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.

Rodriguez and colleagues (2017) noted that CAR T cell therapy has shown great promise in the treatment of hematologic disease, and its utility for treatment of solid tumors is beginning to unfold.  Glioblastoma continues to portend a grim prognosis and immunotherapeutic approaches are being explored as a potential therapeutic strategy.  Identification of appropriate glioma-associated antigens, barriers to cell delivery, and presence of an immuno-suppressive microenvironment are factors that make CAR T cell therapy for glioblastoma particularly challenging.  However, insights gained from pre-clinical studies and ongoing clinical trials indicated that CAR T cell therapy will continue to evolve and likely become integrated with current therapeutic strategies for malignant glioma.

Li and co-workers (2017) stated that neuroblastoma is a childhood cancer that is fatal in almost 50 % of patients despite intense multi-modality treatment.  This cancer is derived from neuroendocrine tissue located in the sympathetic nervous system.  Glypican-2 (GPC2) is a cell surface heparan sulfate proteoglycan that is important for neuronal cell adhesion and neurite out-growth.  These investigators found that GPC2 protein is highly expressed in about 50 % of neuroblastoma cases and that high GPC2 expression correlates with poor OS compared with patients with low GPC2 expression.  They demonstrated that silencing of GPC2 by CRISPR-Cas9 or siRNA resulted in the inhibition of neuroblastoma tumor cell growth.  GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of the target gene N-Myc, an oncogenic driver of neuroblastoma tumorigenesis.  These researchers had isolated human single-domain antibodies specific for GPC2 by phage display technology and found that the single-domain antibodies can inhibit active β-catenin signaling by disrupting the interaction of GPC2 and Wnt3a.  To examine GPC2 as a potential target in neuroblastoma, these investigators developed 2 forms of antibody therapeutics, immunotoxins and CAR T cells.  Immunotoxin treatment was demonstrated to inhibit neuroblastoma growth in mice, whereas CAR T cells targeting GPC2 eliminated tumors in a disseminated neuroblastoma mouse model where tumor metastasis had spread to multiple clinically relevant sites, including spine, skull, legs, and pelvis.  The authors concluded that the findings of this study suggested that GPC2 is a promising therapeutic target in neuroblastoma.

T-Cell Leukemia / Lymphoma

Perera and colleagues (2017) stated that with the emerging success of treating CD19 expressing B-cell malignancies with ex-vivo modified, autologous T cells that express CD19-directed CAR, there is intense interest in expanding this evolving technology to develop effective modalities to treat other malignancies including solid tumors.  Exploiting this approach to develop a therapeutic modality for T cell malignancies for which the available regimens are neither curative, nor confer long-term survival, these researchers generated a lentivirus-based CAR gene transfer system to target the chemokine receptor CCR4 that is over-expressed in a spectrum of T cell malignancies as well as in CD4+ CD25+ Foxp3+ T regulatory cells that accumulate in the tumor microenvironment constituting a barrier against anti-tumor immunity.  Ex-vivo modified, donor-derived T cells that expressed CCR4 directed CAR displayed antigen-dependent potent cytotoxicity against patient-derived cell lines representing adult T cell leukemia/lymphoma (ATL), anaplastic large cell lymphoma (ALCL), cutaneous T cell lymphoma (CTCL), and a subset of HDL.  Furthermore, these CAR T cells also eradicated leukemia in a mouse xenograft model of ATL illustrating the potential utility of this modality in the treatment of a wide spectrum of T-cell malignancies.

Gomes-Silva and associates (2017) noted that extending the success of CAR T cells to T cell malignancies is problematic because most target antigens are shared between normal and malignant cells, leading to CAR T cell fratricide.  CD7 is a transmembrane protein highly expressed in acute T cell leukemia (T-ALL) and in a subset of peripheral T-cell lymphomas.  Normal expression of CD7 is largely confined to T cells and natural killer (NK) cells, reducing the risk of off-target-organ toxicity.  These researchers showed that the expression of a CD7-specific CAR impaired expansion of transduced T cells because of residual CD7 expression and the ensuing fratricide.  They demonstrated that targeted genomic disruption of the CD7 gene prevented this fratricide and enabled expansion of CD7-CAR T cells without compromising their cytotoxic function.  CD7-CAR T cells produced robust cytotoxicity against malignant T cell lines and primary tumors and were protective in a mouse xenograft model of T-ALL.  Although CD7-CAR T cells were also toxic against unedited (CD7+) T and NK lymphocytes, these investigators showed that the CD7-edited T cells themselves can respond to viral peptides and therefore could be protective against pathogens.  The authors stated that genomic disruption of a target antigen overcame fratricide of CAR T cells and established the feasibility of using CD7-CAR T cells for the targeted therapy of T cell malignancies.

Tisagenlecleucel in Combination with Nivolumab for the Treatment of Relapsed / Refractory B-Cell Non-Hodgkin Lymphoma

Cao and colleagues (2019) noted that CAR T cells are emerging as a novel treatment for patients with r/r B-NHL, and combination with PD1 inhibitors may further improve the efficacy of anti-CD19 CAR (CD19 CAR)-T cells in the treatment of lymphomas.  In a single-center study, these researchers examined the safety and efficacy of a combination therapy with CD19 CAR-T cells and nivolumab in patients with r/r B-NHL.  A total of 11 patients with r/r B-NHL were recruited and subsequently received CD19 CAR-T cells and nivolumab.  The primary end-points were safety and feasibility.  The infusions were safe, and no DLT occurred.  Grade 1 or 2 CRS was observed in 25 % (3/11) and 50 % (6/11) of the patients, respectively, and only 1 patient (1/11) experienced neurotoxicity.  The ORR and CR were 81.81 % (9/11) and 45.45 % (5/11), respectively.  The median follow-up time was 6 (1 to 15) months.  The median progression-free survival (PFS) time was 6 months (1 to 14 months), and 3 patients continued to have a response at the time of this writing.  The authors concluded that the findings of this study demonstrated that the combination of CD19 CAR-T cells and nivolumab was feasible and safe and mediated potent anti-lymphoma activity, which should be examined further in prospective clinical trials in r/r B-NHL.  Moreover, these researchers stated that multiple clinical trials examining the combination of CD19 CAR-T cells and anti-PD-1 or anti-PD-L1 antibodies are ongoing.

The authors stated that this study had several drawbacks.  A single-center study and small number of patients recruited (n = 11) made that reasonable statistics analysis unavailable.  Although autologous stem cell transplantation is the standard of therapy for patients with r/r DLBCL, it is marked by high recurrence rates and serious AEs.  Whether combining CD19-CART with anti-PD-1 would be an effective or even preferential strategy by which to cure DLBCL deserves further investigation in larger cohorts with longer-term follow-up.  In addition, the baseline/post-treatment biopsy samples, serum samples and peripheral blood samples were not stored routinely for all patients.  More profound studies with paired tumor samples before and after both CD19 CAR-T monotherapy and combination therapy that compare different clinical responsiveness would facilitate the identification of critical factors and pathways that underling the synergistic antitumor effect of anti–PD-1 and the mechanism of CD19 CAR-T resistance.


Table: ECOG Performance Status
Grade  ECOG
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but amublatory and able to carry out work of a light or secondary nature (e.g., light house work, office work)
2 Ambulatory and capable of all self-care but unable to carry our work activities. Up and about more than 50% of waking hours.
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on self-care. Totally confined to bed or chair
5 Dead

Source: Oken MM,Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.


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