This document 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 hosts.

Cellular therapy (also known as fresh cell treatment) 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:

• Autologous cellular immunotherapy used as a treatment method for prostate cancer is addressed in MED.00106 Autologous Cellular Immunotherapy for the Treatment of Prostate Cancer.
• Donor lymphocyte infusion, used to treat recurrences in individuals 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.
• Melanoma vaccine, a type of immunotherapy used in the treatment of melanoma, is addressed in MED.00083 Melanoma Vaccines.
• There are FDA approved and pharmacopeia recognized off-label uses of interleukin-2 (IL-2) which are not related to adoptive immunotherapy and not addressed by this document.

Investigational and Not Medically Necessary:

Adoptive immunotherapy is considered investigational and not medically necessary in all cases.

Types of adoptive immunotherapy include but are not limited to:

• Adoptive immunotherapy using either tumor-infiltrating lymphocytes (TILs), lymphokine-activated killer (LAK) cells, activated in vitro by recombinant or natural interleukin-2 (IL-2) or other lymphokines, or antigen-loaded dendritic cells,
• Autolymphocyte therapy (ALT), using peripheral T-cells stimulated in vitro by OKT3 monoclonal antibody in conjunction with IL-2. 

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

A randomized trial of LAK therapy in individuals with metastatic renal cell cancer or melanoma unresponsive to standard treatment failed to show that the use of LAK cells provided any health benefit beyond that associated with IL-2 alone (Rosenberg, 1993). Figlin and colleagues (1999) reported the results of a study that randomized 178 subjects 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 those with metastatic renal cell cancer showed promising results (Osband, 1990). Chang and colleagues (2003) reported on the results of another Phase II trial in individuals 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 individual. Of the 39 individuals 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 individuals with malignant melanoma without detectable metastases to receive tumor infiltrating cells and interleukin-2 versus interleukin-2 alone. There was no significant difference 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 individuals 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 two 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 subjects with advanced pancreatic cancer and compared their outcomes to a group of 17 subjects who did not receive LAK cells. The overall survival between the two groups was not different.

In a small open label, non randomized trial, Dillman and colleagues (2009) studied 33 individuals who were treated with intralesional LAK cells as adjuvant therapy for primary glioblastoma (GBM). The study group consisted of 19 men and 14 women with an average age of 57 years. These individuals had previously completed primary therapy for GBM and were without disease progression. The LAK cells were produced by incubating autologous peripheral blood mononuclear cells with IL-2 for 3 to 7 days and then a neurosurgeon placed the LAK cells into the surgically exposed tumor cavity. At the time of the author's analysis, 27 of the individuals had died. The average survival from the date of original diagnosis was 20.5 months with a 1-year survival rate of 75%. In a subset analyses, a higher rate of survival was observed for those who received higher numbers of CD3⁺/CD16⁺/CD56⁺ (T-LAK) cells in the cell products, which was associated with not taking corticosteroids in the month before leukopheresis. The authors noted further evaluation was planned in a randomized phase 2 trial.

Sun and colleagues (2011) investigated the use of expanded activated autologous lymphocyte (EAAL) therapy with CD3⁺CD8⁺ cytotoxic T lymphocyte and CD3^-56⁺ natural killer cell as the major effector. A total of 19 individuals with a variety of metastatic tumors received the EAAL therapy and follow-up data was obtained on all but one individual, who lost contact after the last cell infusion. Upon examination of study results, the authors reported that this therapy failed to delay disease progression in 1/3 of all cases with distant metastases, but noted this approach was worthy of further clinical investigation.

A variety of studies have focused on the use of autologous dendritic cells in a number of malignancies, harvested either from the peripheral blood or the tumor itself and manipulated in various ways. For example, the harvested dendritic cells can be 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 study subjects. Three individuals 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 cervical cancer.

Kim and colleagues (2007), in a phase I/II study, evaluated the feasibility, safety and efficacy of immunotherapy using tumor lysate (TL)-pulsed dendritic cells (DC) in individuals with metastatic renal cell carcinoma (RCC). Nine individuals were administered two cycles of TL-pulsed DC vaccination, which were comprised of four doses injected subcutaneously at biweekly intervals. With a median follow-up of 17.5 months, the median time to disease progression was 5.2 months and the median overall survival was 29 months. The authors concluded immunological monitoring data suggests that the tumor response correlates with the intensity of anti-tumor immunity induced by immunotherapy and further immunological monitoring studies are needed.

Kimura and colleagues (2008), in a prospective phase II study, evaluated the efficacy and toxicity of post surgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from the tissue cultures of tumor draining lymph nodes in individuals with primary lung cancer. The study subjects received 4 courses of chemotherapy along with immunotherapy every 2 months for 2 years. Twenty eight subjects were treated with a total of 313 courses of immunotherapy. The 2 and 5 year survival rates were 88.9% and 52.9%. The authors concluded that large scale phase III studies of this immunotherapy will be necessary before it can be brought into general use.

Kondo and colleagues (2008) studied the clinical efficacy of adoptive immunotherapy on individuals with pancreatic cancer using dendritic cells pulsed with MUC1 peptide (MUC1-DC), and cytotoxic T lymphocyte (CTL) sensitized with a pancreatic cancer, YPK-1, expressing MUC1 (MUC1-CTL). From 2001-2006, 20 subjects with unresectable or recurrent pancreatic cancer were treated. Peripheral blood mononuclear cells (PBMCs) were separated into adherent cells for induction of MUC1-DCs and floating cells for MUC1-CTLs. MUC1-DCs were generated by culture with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) and then exposed to MUC1 peptide and TNF-alpha. MUC1-CTLs were induced by co-culture with YPK-1 and then with interleukin-2 (IL-2). MUC1-DCs were injected intradermally and MUC1-CTLs were given intravenously. Subjects were treated from 2 to 15 times. One individual who had had multiple lung metastases after curative surgery experienced a complete response and five had stable disease. The mean survival time was 9.8 months. The authors noted that further randomized controlled studies of large numbers of patients are needed to confirm the efficacy of this combination adoptive immunotherapy for pancreatic cancer.

According to the American Cancer Society (ACS) (2010):

LAK cell therapy has shown promising results in animal studies, where it shrunk tumors in animals with lung, liver, and other cancers. Although clinical trials in humans have not yet been as successful, researchers are constantly improving LAK cell techniques. They are testing these newly improved methods against melanoma, brain tumors, and other cancers.

The ACS (2010) states in regards to TIL therapy: "Success with TILs in lab animals has led researchers to try to increase the anti-tumor activity of TILs. Treatments using TILs are being tested in clinical trials in people with melanoma, kidney cancer, and other cancers."

The ACS (2008) states in regards to cellular therapy:

Available scientific evidence does not support claims that cell therapy is effective in treating cancer or any other disease. Serious side effects can result from cell therapy. In fact, it may be lethal-several deaths have been reported. It is important to distinguish this alternative method involving animal cells from mainstream cancer treatments that use human cells, such as bone marrow transplantation.

Although multiple clinical trials focusing on different types of malignancies and adoptive immunotherapy exist, there is insufficient evidence demonstrating its safety and efficacy. With respect to cellular therapy there is a lack of clinical information and scientific evidence in the published literature to support the use of this procedure. At this time, the safety and efficacy of both adoptive immunotherapy and cellular therapy are not supported in the peer reviewed scientific literature.

The spontaneous regression of certain cancers, such as renal cell cancer or melanoma, supports the idea that an individual's immune system is sometimes capable of delaying tumor progression and on rare occasions can eliminate the tumor altogether. These observations have led to research interest in a variety of immunologic therapies designed to stimulate an individual'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 individuals. Techniques of adoptive immunotherapy which have been explored include:

1. Lymphokine-activated killer (LAK) cell therapy:  The individual'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. (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 individual. 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 individual'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 individual. 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, 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. There is 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.

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:  Within a glass, petri dish or test tube; in an artificial environment; outside of the body.

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 individuals 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: Is 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.

The following codes for treatments and procedures applicable to this document 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 and Not Medically Necessary:
For the following procedure codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary

Peer Reviewed Publications:

1. 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.
2. 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.
3. 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.
4. 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.
5. Dillman RO, Duma CM, Ellis RA, et al. Intralesional lymphokine-activated killer cells as adjuvant therapy for primary glioblastoma. J Immunother. 2009; 32(9):914-919.
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. Kim JH, Lee Y, Bae YS, et al. Phase I/II study of immunotherapy using autologous tumor lysate-pulsed dendritic cells in patients with metastatic renal cell carcinoma. Clin Immunol. 2007; 125(3):257-267
13. Kimura H, Iizasa T, Ishikawa A. Prospective phase II study of post-surgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue culture of tumor-draining lymph nodes in primary lung cancer patients. Anticancer Res. 2008; 28(2B):1229-1238.
14. Klingemann HG. Cellular therapy: Finishing the job. J Hematother and Stem Cell Res. 2001; 10:435-436.
15. Klingemann HG. Cellular therapy of cancer with natural killer cells: Will it ever work? J Hematother Stem Cell Res. 2001; 10:23-26.
16. 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.
17. Kondo H, Hazama S, Kawaoka T, et al. Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res. 2008; 28(1B):379-387.
18. 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.
19. 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.
20. 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. 
21. Link CJ, Seregina T, Traynor A. Cellular suicide therapy of malignant disease. Stem Cells. 2000; 18:220-226.
22. Osband ME, Lavin PT, Babayan RK, et al. Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma. Lancet. 1990; 335(8696):994-998.
23. Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst. 1993; 85(8):622-632.
24. 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.
25. 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.
26. Stift A, Friedl J, Dubsky P,et al. Dendritic cell-based vaccination in solid cancer. J Clin Oncol. 2003; 21:135-142.
27. Sun Z, Shi L, Zhang H, et al. Immune modulation and safety profile of adoptive immunotherapy using expanded autologous activated lymphocytes against advanced cancer. Clin Immunol. 2011; 138(1):23-32.
28. 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.
29. Thiounn T, Pages F, Medjean A. Adoptive immunotherapy for superficial bladder cancer with autologous macrophage activated killer cells. J Urol. 2002; 168:2373-2376.
30. 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.
31. 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.
32. 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.
33. 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. American Cancer Society. Cell therapy. Revised November 1, 2008. Available at: http://www.cancer.org/docroot/ETO/content/ETO_5_3X_Cell_Therapy.asp?sitearea=ETO. Accessed on March 22, 2011.
2. American Cancer Society. Other active specific immunotherapies. Revised October 12, 2010. Available at: http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Immunotherapy/immunotherapy-active-specific-immunotherapies. Accessed on March 22, 2011.
3. American Cancer Society. What is immunotherapy? Revised October 12, 2010. Available at: http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Immunotherapy/immunotherapy-what-is-immunotherapy. Accessed on March 22, 2011.
4. Centers for Medicare and Medicaid Services. National Coverage Determination for Cellular Therapy. NCD #30.8. Effective date not posted. Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=6&ncdver=1&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyWord=cellular+therapy&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAACAAAAAA&. Accessed on March 22, 2011.

Adoptive Immunotherapy
Autolymphocyte Therapy
Cell Therapy
Embryonic Cell Therapy
Fresh Cell Therapy
Glandular Therapy
Live Cell Therapy
Lymphokine-Activated Killer Cell Therapy
Organotherapy
Passive Non-Specific Immunotherapy
Passive Specific Immunotherapy
Tumor-Infiltrating Lymphocyte Therapy
Zellen-Cell Therapy (Pills)