This policy addresses adoptive immunotherapy and cellular therapy.  Adoptive immunotherapy is a general term describing the transfer of immunocompetent cells (i.e., lymphocytes) 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.

Cellular therapy involves the injection or ingestion of tissue (e.g., cartilage, embryonic, organs, fetal, glandular) obtained from animal (e.g., sheep, cow and shark) tissues.  It has been proposed as a treatment of AIDS, arthritis, asthma, chronic fatigue, cancer, diabetes, hypertension, colonic diverticulum as well as other conditions or diseases.

Note:  Donor lymphocyte infusion, used to treat recurrences in patients who have undergone an allogeneic transplant, is a form of adoptive immunotherapy and is addressed in TRANS.00018 Donor Lymphocyte Infusion for Hematologic Malignancies after Allogeneic Stem Cell Transplantation.

Investigational/Not Medically Necessary:

Adoptive immunotherapy, using either tumor-infiltrating lymphocytes, lymphokine-activated killer (LAK) cells, activated in vitro by recombinant or natural interleukin-2 (IL-2) or other lymphokines, or antigen-loaded dendritic cells, is considered investigational/not medically necessary in malignancies, including but not limited to advanced renal cell carcinoma, melanoma, or breast cancer.

Autolymphocyte therapy (ALT) using peripheral T-cells stimulated in vitro by OKT3 monoclonal antibody in conjunction with IL-2 is considered investigational/not medically necessary.

Other applications of adoptive immunotherapy are considered investigational/not medically necessary.

Cellular therapy (also known as fresh cell treatment) is considered investigational/not medically necessary in all cases.

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.  Figlin and colleagues (1999) 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 tumor-infiltrating lymphocyte (TIL) cells. 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. The therapy is designed to delay or prevent metastatic recurrence in patients with high-risk renal cell cancer.  Chang and colleagues (2003) 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.  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 that participated in the trial, there were four complete responses and five partial responses.  Dreno and colleagues (2002) 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.  There was no significant different in the duration of the relapse-free interval or overall survival.

Studies have also examined the role of adoptive immunotherapy for hepatocellular cancer (HCC) and pancreatic cancer.  Takayama and colleagues (2000) 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. The immunotherapy consisted of five 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 (2000) 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. 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.

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 (Small, 2000).  In the treatment of hormone refractory prostate cancer, Small and colleagues (2000) explored the use of autologous dendritic cells exposed in vitro to prostatic acid phosphatase. 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, myeloma, subcutaneous tumors, melanoma, renal cell cancer, and cervix, but no controlled trials were identified in a literature search.

Mackensen and colleagues (2006) conducted a phase I study to test the feasibility, safety, and survival of adoptively transferred Melan-A–specific CTL (cytotoxic T lymphocytes) lines in melanoma patients. CTL were generated by in vitro stimulation of peripheral blood lymphocytes with autologous dendritic cells. Each T-cell infusion was accompanied by a course of low-dose interleukin-2. infusion. Clinical and immunologic responses revealed an antitumor response in three of 11 patients (one complete regression, one partial regression, one mixed response. Additional study with a larger number of patients is required to draw any conclusions regarding the safety and efficacy of this procedure.

Currently, there are several phase I and II trials focusing on different types of malignancies and different types of immunotherapy, however there is inadequate scientific and clinical research information available in peer-reviewed medical publications to support the safety, effectiveness, and utility of cellular therapy at this time.

Background/Overview

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 patent’s own immune systems, which can be categorized as follows:  (1) active non-specific immunotherapy, i.e., the use of interleukin-2;  (2) active specific immunotherapy, e.g., immunization with a variety of therapeutic vaccines;  (3) passive non-specific immunotherapy, i.e., transfer of lymphokine-activated killer cells; and  (4) passive specific immunotherapy; i.e., transfer of specific immune cells such as cytotoxic T-lymphocytes or lymphocytes producing specific antibodies.  Adoptive immunotherapy is a general term describing the transfer of immunocompetent cells (i.e., lymphocytes) to the tumor-bearing host and thus would include the latter two strategies listed above.

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.  The following three techniques of adoptive immunotherapy have been explored:

1. Lymphokine-activated killer (LAK) cell therapy:  The patient's peripheral blood lymphocytes (obtained via multiple leukaphereses) are treated with interleukin-2 (IL-2) in vitro to produce LAK cells; these treated cells are subsequently reinfused into the patient.  (IL-2 is a cytokine produced by lymphocytes and is a growth and activation factor for both T-cells and natural killer cells.) 
   
   
2. Tumor-infiltrating lymphocyte (TIL) therapy:  The lymphocytes infiltrating a tumor are both cytotoxic and helper T cells and have been shown to have specific antitumor activity, presumably because they recognize specific tumor antigens.  TIL therapy involves harvesting the tumor-infiltrating lymphocytes from the tumor itself and then isolating the cells by growing single-cell suspensions from the tumor.  After several weeks of culture in the presence of IL-2, the activated TIL cells are transfused back into the patient.  This technique may require an additional biopsy procedure for the sole purpose of harvesting a portion of tumor for subsequent isolation of the TILs.
   
   
3. Transfer of specific immune cells:  In this multistep outpatient procedure, the patient’s T-cell lymphocytes or dendritic cells, collected through a pheresis procedure, are exposed to a variety of immunogenic stimuli.  For example, in autolymphocyte therapy (ALT), harvested T cells are exposed to a combination of OKT3 monoclonal antibodies and IL-2.  The OKT3 antibody is thought to activate memory T cells, which theoretically have been exposed to tumor-associated antigens.  The IL-2 is used for clonal expansion of the memory T cells.  These cells are then reintroduced into the patient.  The treatment is repeated each month for 6 months or longer.  In another variant, collected dendritic cells are exposed to a variety of antigens, such as prostatic acid phosphatase.  When reinfused into the patients, these dendritic cells function as potent immunostimulators of native T cells.

The intended purpose of cellular therapy is to transfer immunity or anti-disease attributes from one organism to another through the sharing of cells that are believed to impart such characteristics to the donor organism.  There is very little published information available on cellular therapy and its proposed mechanisms of action.  The FDA has received reports of viral and microbial infections, allergic reactions, anaphylactic shock and death following cell therapies.

Definitions

Anaphylactic shock: an allergic reaction that produces life-threatening changes in the circulation and air passages

Dendritic cell:  a special type of antigen-presenting cell (APC) that activates T lymphocytes

Immunity: the state of being immune to or protected from a disease, especially an infectious disease

Interleukin-2 (IL-2): one type of a chemical messenger from the family of interleukins, which are substances that can improve the body’s response to disease; IL-2 stimulates the growth of certain disease-fighting blood cells in the body

In vitro: outside the living body and in an artificial environment, such as a laboratory

Lymphocyte: a small white blood cell that plays a large role in defending the body against disease

Lymphokine-activated (LAK) cells: blood cells that are collected from patients with tumors and treated in a laboratory with IL-2 to make them work more efficiently against the tumor when injected back into the body

Melanoma: the most dangerous form of skin cancer caused by mutation of a cell that produces pigment in the skin called a melanocyte

Monoclonal antibody: an antibody produced by a single clone of a cell, which is grown in a lab to attach to or fight specific cells in the body

Peripheral T-cells: a type of cell that fights diseases in the blood

Coding

The following codes for treatments and procedures applicable to this policy are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational/Not Medically Necessary:
For the following procedure codes, or when the code describes a procedure indicated in the Policy section as investigational/not medically necessary

HCPCS

ICD-9 Diagnosis

References

Peer Reviewed Publications:

1. American Cancer Society. Unproven methods of cancer management: fresh cell therapy. CA. 1991;41(2):126-128.
2. Banchereau J, Ueno H, Dhodapkar M, et al. Immune and clinical outcomes in patients with stage IV melanoma vaccinated with peptide-pulsed dendritic cells derived from CD34+ progenitors and activated with type I interferon. J Immunother. 2005; 28(5):505-516.
3. Cassidanius A, Lemarre P, Billaudel S, et al. Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother. 2002; 51(10):539-546. 
4. Chang AE, Li Q, Jiang G, et al. Phase II trial of autologous tumor vaccination, anti-CD-3-activated vaccine-primed lymphocytes and interleukin-2 in stage IV renal cell cancer.  J Clin Oncol. 2003; 21:884-890.
5. Deeks SG, Wagner B, Anton PA, et al. A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol Ther. 2002; 5(6):788-797.
6. Dreno B, Nguyen JM, Khammari A, et al. Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother. 2002; 51(10):539-546. 
7. Dudley ME, Wunderlich J, Nishimura MI, et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother. 2001; 24(4):363-373. 
8. Dudley ME, Wunderlich J, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005; 23(10):2346-2357.
9. Figlin RA, Thompson JA,et al. Multicenter, randomized phase III trial of CD8+ tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999; 17(8):2521-2529.
10. Gardini A, Ercolani G, et al. Adjuvant, adoptive immunotherapy with tumor infiltrating lymphocytes plus interleukin-2 after radical hepatic resection for colorectal liver metastases: 5-year analysis. J Surg Oncol. 2004 Jul 15; 87(1):46-52.
11. Katano M, Morisaki T, Koga K, et al. Combination therapy with tumor cell-pulsed dendritic cells and activated lymphocytes for patients with disseminated carcinomas. Anticancer Res. 2005; 25(6A): 3771-3776.
12. Klingemann HG. Cellular therapy: Finishing the job. J Hematother and Stem Cell Res. 2001; 10:435-436.
13. Klingemann HG. Cellular therapy of cancer with natural killer cells: Will it ever work? J Hematother Stem Cell Res. 2001; 10:23-26.
14. Kobari M, Egawa S,et al. Effect of intraportal adoptive immunotherapy on liver metastases after resection of pancreatic cancer. Br J Surg. 2000; 87(1):43-48.
15. Labarriere N, Pandolfino MC, Gervois N, et al. Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients. Cancer Immunol Immunother. 2002; 51(10):532-538. 
16. Lee WC, Wang HC, Hung CF, Huang PF, et al. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother. 2005; 28(5):496-504.
17. Levine BL, Bernstein WB, Aronson NE, et al. Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med. 2002; 8(1):47-53.  
18. Link CJ, Seregina T, Traynor A. Cellular suicide therapy of malignant disease. Stem Cells. 2000; 18:220-226.
19. Mackensen A, Meidenbauer N, Vogl S, et al. Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. J Clin Oncol. 2006; 24(31): 5060-5069.
20. Santin AD, Bellonw S, Palmieri M et al. Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix. Gynecol Cancer. 2003; 89:271-280.
21. Small EJ, Fratesis P, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol. 2000; 18(23):3894-3903.
22. Stift A, Friedl J, Dubsky P,et al. Dendritic cell-based vaccination in solid cancer. J Clin Oncol. 2003; 21:135-142.
23. Takayama T, Sekine T,et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomized trial. Lancet. 2000; 356(9232):802-807.
24. Thiounn T, Pages F, Medjean A. Adoptive immunotherapy for superficial bladder cancer with autologous macrophage activated killer cells. J Urol. 2002; 168:2373-2376.
25. Tsoukas CM, Turner HM, Hatzakis GE, et al. Improvement of HIV-specific immunity in HIV-infected twins treated with highly active antiretroviral therapy, interleukin 2, and syngeneic adoptively transferred cells. AIDS Res Hum Retroviruses. 2001; 17(10):887-900.
26. Walker RE, Bechtel CM, Natarajan V, et al. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood. 2000; 96(2):467-474.
27. Wood GW, Holladay FP, Turner T, et al. A pilot study of autologous cancer cell vaccination and cellular immunotherapy using anti-CD3 stimulated lymphocytes in patients with recurrent grade III/IV astrocytoma. J Neuro-Oncology. 2000; 48:113-120.
28. Yee C, Thompson JA, Byrd D, et al. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci U S A. 2002; 99(25):168-173.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Centers for Medicare and Medicaid Services. National Coverage Determination for Cellular Therapy. NCD #30.8. Effective date not posted. Available at: 
   http://www.cms.hhs.gov/mcd/viewncd.asp?ncd_id=30.8&ncd_version=1 &basket=ncd%3A30%2E8%3A1%3ACellular+Therapy. Accessed on February 15, 2007.
   

Web Sites for Additional Information

1. American Cancer Society.  Cell therapy. Revised June 1, 2005. Available at:
   http://www.cancer.org/docroot/ETO/content/ETO_5_3X_Cell_Therapy.asp?sitearea=ETO. Accessed on February 14, 2007.
2. American Cancer Society. Other active specific immunotherapies. Revised December 14, 2006. Available at:   http://www.cancer.org/docroot/ETO/content/ETO_1_4X_ Other_Active_Specific_Immunotherapies.asp?sitearea=ETO. Accessed on February 14, 2007.
3. American Cancer Society. What is immunotherapy? Revised December 14, 2006. Available at:
   http://www.cancer.org/docroot/ETO/content/ETO_1_4X_ What_Is_Immunotherapy.asp?sitearea=ETO. Accessed on February 14, 2007..

Index

Policy History

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member's contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by an means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

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