MP 8.01.01

Adoptive Immunotherapy

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Medical Policy
Section Therapy	Original Policy Date 12/1/96	Last Review Status/Date Reviewed with literature search/11:2008
Issue 11:2008		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

The spontaneous regression of certain cancers, such as renal cell cancer or melanoma, supports the idea that the patient’s immune system is sometimes capable of delaying tumor progression and, on rare occasions, can eliminate the tumor altogether. These observations have lead to research interest in a variety of immunologic therapies designed to stimulate the patient’s own immune systems. Adoptive immunotherapy is the transfer of previously sensitized immunologic cells (e.g., cytotoxic T-lymphocytes or lymphocytes producing specific antigens) to the tumor-bearing host.

The major research challenge in adoptive immunotherapy is to develop immune cells with specific anti-tumor reactivity that could be generated in large enough quantities for transfer to tumor-bearing patients. In current trials, these cells are transferred either using adoptive cellular therapy (ACT), or through antigen-loaded dendritic cell infusions.

ACT protocols vary, but include these common steps:

Initially, lymphokine-activated killer (LAK) cells were harvested peripherally and activated in vitro with interleukin-2 (IL-2) and other cytokines. More recent techniques include the use of autologous dendritic cells (ADC) or tumor-infiltrating lymphocytes (TIL). If the lymphocytes are harvested from peripheral blood, autologous dendritic cells (ADC) pulsed with tumor antigens are used to propagate the lymphocytes. If the lymphocytes are harvested from the tumor biopsy, these tumor-infiltrating lymphocytes (TIL) are propagated with IL-2 and OKT3.

In an attempt to further regulate the host immune system, recent protocols differ in the types of cytokines (IL-7 and IL-15 instead of IL-2) used to propagate lymphocytes. They also differ in the extent of lymphodepletion used prior to transfusing the lymphocytes to the tumor-bearing host.

Note: Donor leukocyte infusion, used to treat leukemia recurrences in patients who have undergone an allogeneic transplant, is another form of adoptive immunotherapy addressed in a separate policy, No. 2.03.03. In addition, non-myeloablative allogeneic stem-cell transplantation (reduced-intensity conditioning, RIC) relies on a donr-versus-malignancy effect of donor lymphocytes; this may be referred to as adoptive immunotherapy in the literature. The use if RIC stem-cell transplantation is outlined for specific cancers in individual policies. Tumor vaccines are a type of immunotherapy that are considered in a separate policy, No. 2.03.04. Interleukin-2 therapy is addressed in policy No. 8.01.04.

Policy

Policy Guidelines

Benefit Application

Rationale

A randomized trial of LAK therapy in patients with advanced cancer failed to show that the use of LAK cells provided any health benefit beyond that associated with IL-2 alone. (1) Figlin and colleagues reported the results of a study that randomized 178 patients with metastatic renal cell cancer and resectable renal tumors to receive adjunctive continuous low-dose IL-2 therapy, with or without additional TIL cells. (2) The TIL cells were harvested from the surgical specimens. The outcomes were similar in both groups, and for this reason the study was terminated early. Early studies of autolymphocyte therapy (ALT) in patients with metastatic renal cell cancer showed promising results (3); the manufacturers of ALT therapy are currently pursuing FDA approval through the treatment IND process, but as yet this therapy has not received FDA approval. A search of the PDQ clinical trials database identified one active phase II trial in which ALT was administered as an adjuvant to surgical resection in patients with nonmetastatic renal cell cancer. (4) Chang and colleagues reported on the results of another phase II trial in patients with stage IV renal cell cancer who received irradiated autologous tumor cells admixed with Calmett-Guerin bacillus. (5) Seven days later, vaccine-primed lymph nodes were harvested, and the lymphoid cells secondarily activated and then infused back into the patient. Of the 39 patients who participated in the trial, there were 4 complete responses and 5 partial responses. Dreno and colleagues reported on the results of a trial that randomized 88 patients with malignant melanoma without detectable metastases to receive tumor-infiltrating cells and interleukin-2 versus interleukin-2 alone. (6) There was no significant difference in the duration of the relapse-free interval or overall survival.

 

Recent studies have also examined the role of adoptive immunotherapy for hepatocellular cancer (HCC) and pancreatic cancer. Takayama and colleagues conducted a study that randomized 150 patients who had undergone a curative resection for HCC to receive either adjuvant adoptive immunotherapy or no additional treatment. (7) The immunotherapy consisted of 5 injections over 24 weeks of autologous T cells, harvested from the peripheral blood, and cultured for 2 weeks with IL-2. The immunotherapy group had significantly longer recurrence-free survival and disease-specific survival, but the overall survival, the final health outcome, did not differ significantly between the two groups. Kobari and colleagues describe the use of intraportal injections of lymphokine-activated killer (LAK) cells after tumor resection in 12 patients with advanced pancreatic cancer and compared their outcomes to a group of 17 patients who did not receive LAK cells. (8) The overall survival between the two groups was not different. LAK cells have also been investigated as a treatment of malignant glioma and bladder cancer but no controlled trials have been published. (9-11)

 

A variety of studies have focused on the use of autologous dendritic cells in a variety of malignancies, harvested either from the peripheral blood or the tumor itself and manipulated in a variety of ways. For example, the harvested dendritic cells can by exposed to pulses of tumor lysate. (12) In the treatment of hormone refractory prostate cancer, Small and colleagues explored the use of autologous dendritic cells exposed in vitro to prostatic acid phosphatase. (13) These “antigen-loaded” dendritic cells are thought to have a potent capacity to stimulate specific T-cell responses. In phase I and II trials, Small reported that the therapy was well tolerated and that specific immune responses were induced in all patients. Three patients exhibited a clinical response, as evidenced by a greater than 50% decrease in PSA levels. Antigen-loaded dendritic cells have been explored in other malignancies including lymphoma (14), myeloma, (15, 16) subcutaneous tumors (17), melanoma (18), renal cell cancer, (19) and uterine cervical cancer (20), but no controlled trials were identified in a literature search.

 

2006 Update

A search of the literature for the period of 2003 through January 2006 did not identify any published studies that would prompt reconsideration of the policy statement; therefore, the policy is unchanged. A search of the clinical trials database (www.clinicaltrials.gov) maintained by the National Institutes of Health using the key search term “adoptive immunotherapy” identified several phase I and II trials focusing on different types of malignancies and different types of immunotherapy. In general, these trials involved collecting autologous T cells in a pheresis procedure, or extracted from the tumor itself, expanding the clone in vivo using different immunomodulatory stimuli, and then reinfusing the cells back into the patient. For example, a phase I/II trial in patients with recurrent CML after a prior allogeneic bone marrow transplant reinfused CD8+ proteinase-3 specific cytotoxic T-lymphocyte clones. A phase I/II study of acute AML is investigating an infusion of CD+ Wilms’ gene-specific T lymphocytes. However, all of the posted trials were early phase I or II studies.

 

2008 Update
A literature search was performed using MEDLINE through August 2008 for the search terms, “adoptive immunotherapy” or “tumor-infiltrating lymphocytes”. In the current search, a post-hoc analysis (21) of the adjuvant LAK therapy proposed by Rosenberg et al. (1) found survival benefit in stage III melanoma with one tumor-invaded lymph node. However, this study has not been reproduced. Other studies are evaluating the use of different lymphodepleting preparations, the cloning or in vitro sensitization of highly avid antigen-reactive cells, and the use of gene therapy to promote anti-tumor activity. (22)

Lymphodepleting preparations
In an analysis of 25 patients who were treated with TIL, Robbin et al. (23) demonstrated a correlation between tumor regression and the degree of persistent T-cells in the peripheral blood prior to the leukocyte infusion. Patients with few preinfusion lymphocytes in their peripheral blood had better tumor response than those who had many lymphocytes in their peripheral blood. Ongoing trials with nonmyeloablative lymphodepleting agents have demonstrated partial and complete tumor response at 3- to 5-year follow-up in patients with advanced-stage melanoma. (24)

Cloned or in vitro sensitized peripheral blood leukocytes
Other techniques include the use of autologous peripheral blood mononuclear cells from metastatic melanoma patients with highly avid CD-8 binding peptides (25), and autologous dendritic cells pulsed with tumor-specific antigens. (26) Unfortunately, these studies lacked sufficient potency and few patients exhibited complete or partial tumor response. This technique has been studied in numerous solid tumors including lung (27), pancreatic (28), brain glioma (29), and renal cell (30) cancers.

T-cell receptor gene therapy
Because the method for adoptive cell transfer therapy is technically and logistically demanding, alternate methods using genetic engineering are being explored. Using retroviral-based vectors, genes for tumor-specific antibodies are grafted with the melanoma patient’s lymphocytes and transfused back into the patient. (31)

National Cancer Institute’s (NCI) Physician Data Query (PDQ) and the National Institutes of Health’s (NIH) Clinical Trials Database

 

In the NIH’s clinical trial database (www.clinicaltrials.gov) there are 7 active and 8 recruiting Phase I/II trials investigating the use of adoptive immunotherapy in solid tumors.

There are 24 ongoing trials on adoptive immunotherapy in the PDQ database: http://www.cancer.gov/search/ResultsClinicalTrialsAdvanced.aspx?protocolsearchid=5113671#

Data do not permit conclusions about the impact on clinical outcomes (overall survival); therefore, the use of adoptive immunotherapy remains investigational. The policy statements remain unchanged.

 

References:

 

Policy History

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