Aetna considers adoptive immunotherapy, using either tumor-infiltrating lymphocytes (TILs) or lymphokine-activated killer (LAK) cells that are activated in vitro by interleukin-2 (IL-2), experimental and investigational for treatment of renal cell carcinoma, melanoma, esophageal cancer, breast cancer, lung cancer, pancreatic cancer, or other malignancies due to lack of adequate evidence that it is as beneficial as IL-2 alone. 

Aetna considers adoptive immunotherapy experimental and investigational for all other indications, including Alzheimer disease, other amyloid disorders, sporadic inclusion-body myositis, intractable viral diseases, and other infectious diseases.

See also CPB 377 - Dendritic Cell Immunotherapy, and CPB 638 - Donor Lymphocyte Infusion.

Adoptive immunotherapy involves removing lymphocytes from the patient, boosting their anti-cancer activity, growing them in large numbers, and then returning them to the patient:

LAK cells: Initial experiments in adoptive immunotherapy involved removing lymphocytes from the blood of a patient and growing them in the presence of the lymphokine interleukin-2 (IL-2), an immune stimulator. The cells were then returned to the patient. These lymphocytes were called lymphokine-activated killer (LAK) cells.

TILs: A stronger response against tumor cells is obtained using lymphocytes isolated from the tumor itself. These tumor-infiltrating lymphocytes (TILs) are grown in the presence of IL-2 and returned to the body to attack the tumor. Researchers are also using radiolabeled monoclonal antibodies for tumor antigens to even more closely identify lymphocytes specific for tumor cells.

Adoptive immunotherapy and dendritic cell immunotherapy are forms of cellular therapy, where ex vivo processed cells are introduced into the body. Adoptive immunotherapy uses immune effector cells (e.g., T cells), whereas dendritic cell immunotherapy uses antigen-presenting cells.

Pre-clinical studies suggested anti-tumor activity could be enhanced by using interleukin-2 together with ex vivo activated and expanded autologous lymphocytes. Also, the first objective responses with high-dose bolus interleukin-2 therapy were noted in patients receiving interleukin-2 together with LAK cells prepared through in vitro activation of autologous peripheral blood lymphocytes that were harvested by lymphopheresis, and initially, it appeared that the combination of interleukin-2/LAK was more active than interleukin-2 alone.

Clinical studies have failed to demonstrate that the addition of activated LAK cells with IL-2 is any more effective than IL-2 alone. Major IL-2/LAK clinical trials in patients with renal cell carcinoma have been conducted by several groups, including the National Cancer Institute (NCI) Surgery Branch, the Interleukin-2/LAK Working Group, and the NCI-sponsored Modified Group C centers. A subset of the NCI Surgery Branch's patients with renal cell carcinoma and with all patients entered into the Modified Group C trials were randomized to receive IL-2 alone or together with LAK cells. Response rates to IL-2 used alone and together with LAK cells as well as durability of responses did not differ substantially. In a review of the literature, Grimm (2000) concluded that “the data do not support a major contribution of ex vivo activated and adoptively transferred LAK cells to the efficacy of high-dose bolus IL-2 in patients with renal cell carcinoma.”

Similar conclusions were reached regarding the adoptive transfer of LAK cells in patients with melanoma treated with high-dose bolus IL-2. Response rates with IL-2/LAK are not different from those observed with high-dose IL-2 alone, and IL-2/LAK therapy in other solid tumors has been disappointing. While attempts to generate LAK at the tumor site remain attractive, Grimm (2000) concluded that the intravenous infusion of LAK is not likely to prove effective in cases beyond the blood-borne metastatic deposits, which appear just as sensitive to interleukin alone.

Grimm (2000) notes that clinical trials conducted with IL-2 and tumor infiltrating lymphocytes (TIL) has also been disappointing. Clinical trials of IL-2/TIL have been performed on the basis of the theory that tumor infiltrating lymphocytes would include those with tumor specific activity, which was somehow suppressed in the vicinity of the tumor. These lymphocytes are produced by placing digested, fresh tumor biopsies into an in vitro culture with IL-2. Although some early studies have noted response rates using TIL cells together with IL-2 in the 30 to 40% range, there are no studies comparing responses with TIL cells compared with IL-2 alone.

A Cochrane meta-analysis examined the published evidence for adoptive immunotherapy in renal cell cancer (Coppin, et al., 2004).  The investigators identified one study that compared high dose IL-2 plus LAK cells with high dose IL-2 alone (Rosenberg, et al., 1993). Three other studies examined IL-2 given in modified schedules to reduce toxicity but with additions intended to maintain or improve efficacy compared to the high dose IL-2 regimen. The modifiers included TILs (Figlin, et al., 1999), or LAK cells (McCabe, et al., 1991; Law, et al., 1995). The investigators found that examination of individual and pooled response rates showed no clear evidence of enhancement for remission (Peto OR 0.93, 95% confidence interval 0.50 to 1.74) (Coppin, et al., 2004). Likewise for the three studies reporting survival, one-year mortality was not reduced (Peto OR 0.78, 95% confidence interval 0.50 to 1.21).

In a phase II clinical study, Kimura and associates (2008) evaluated the effectiveness and toxicity of adjuvant chemo-immunotherapy using dendritic cells and activated killer cells are in post-surgical primary lung cancer patients (n = 31). The activated killer cells and dendritic cells (AKT-DC) obtained from tissue cultures of tumor-draining lymph nodes (TDLN) or from TDLN co-cultured with peripheral blood lymphocytes (TDLN-Pb) were used for the adoptive transfer of immunotherapy. Patients received 4 courses of chemotherapy along with immunotherapy every 2 months for 2 years. Three cases were excluded because of refusal by the patients after 1 to 2 courses of immunotherapy. For the 28 cases treated, a total of 313 courses of immunotherapy were administered. The main toxicities were fever (78.0 %), chill (83.4 %), fatigue (23.0 %) and nausea (17.0 %) on the day of cell transfer. The 2- and 5-year survival rates were 88.9 % (95.9 to 81.9; 95 % confidence interval, C.I.) and 52.9 % (76.4 to 29.4; C.I.). The authors concluded that adoptive transfer of activated killer cells and dendritic cells from the tumor-draining lymph nodes of primary lung cancer patients is feasible and safe, and a large-scale multi-institutional study is needed for assessing the effectiveness of this treatment.

Bernhard and colleagues (2008) stated that the human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated antigen by immuno-therapeutical approaches based on HER2-directed monoclonal antibodies and cancer vaccines. These investigators described the adoptive transfer of autologous HER2-specific T-lymphocyte clones to a patient with metastatic HER2 over-expressing breast cancer. The HLA/multimer-based monitoring of the transferred T lymphocytes revealed that the T cells rapidly disappeared from the peripheral blood. The imaging studies indicated that the T cells accumulated in the bone marrow (BM) and migrated to the liver, but were unable to penetrate into the solid metastases. The disseminated tumor cells in the BM disappeared after the completion of adoptive T-cell therapy. The findings of this study suggest the therapeutic potential for HER2-specific T cells for eliminating disseminated HER2-positive tumor cells and propose the combination of T cell-based therapies with strategies targeting the tumor stroma to improve T-cell infiltration into solid tumors.

Adoptive immunotherapy is also being studied as a means for treating non-malignant conditions such as amyloid disorders (e.g., Alzheimer disease, sporadic inclusion-body myositis) and infectious diseases/intractable viral diseases.  However, there is currently insufficient evidence to support the clinical value of these potential applications of adoptive immunotherapy.