Medical Policy

This document addresses adoptive immunotherapy and cellular therapy. Adoptive immunotherapy is a general term describing the transfer of immunocompetent cells (for example, 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 the tumor-bearing host.

Cellular therapy (also known as fresh cell treatment) involves the injection or ingestion of tissue (for example, cartilage, embryonic, organs, fetal, glandular) obtained from animal (for example, sheep, cow and shark) tissues. It has been proposed as a treatment of acquired immune deficiency syndrome, 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 individuals who have undergone an allogeneic transplant, is a form of adoptive immunotherapy and is addressed in CG-TRANS-03 Donor Lymphocyte Infusion for Hematologic Malignancies after Allogeneic Hematopoietic Progenitor Cell Transplantation.
• There are United States Food and Drug Administration (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 tumor-infiltrating lymphocytes, lymphokine-activated killer cells, activated in vitro by recombinant or natural interleukin-2 or other lymphokines, or antigen-loaded dendritic cells, or cytokine-induced killer cells.
• Autolymphocyte therapy, using peripheral T-cells stimulated in vitro by OKT3 monoclonal antibody in conjunction with interleukin-2.

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

An early randomized trial of lymphokine-activated killer (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 interleukin-2 (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 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 TIL cells and IL-2 versus IL-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 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 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 analysis, 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 II 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 cells 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 1 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 one-third of all cases with distant metastases, but noted this approach was worthy of further clinical investigation.

Zhang and colleagues (2015) conducted a retrospective analysis of clinical data involving 84 individuals with gastric cancer. In this group, 42 subjects were treated with EAAL and conventional therapy and another 42 were treated with conventional therapy only. The cohort was studied retrospectively to evaluate the relationship between treatment and overall survival (OS) data obtained for both groups. Overall survival in the group having surgery and EAAL was prolonged after EAAL immunotherapy (p<0.05). The authors concluded that prospective cohort clinical studies with larger sample sizes are required for confirmation of their findings.

A variety of studies have focused on the use of autologous dendritic cells (DC) in a number of malignancies, harvested either from the peripheral blood or the tumor itself and manipulated in various ways. For example, the harvested DC 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 DC exposed in vitro to prostatic acid phosphatase. These “antigen-loaded” DC 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 prostate-specific antigen (PSA) levels. Antigen-loaded DC 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 DC in individuals with metastatic renal cell carcinoma (RCC). Nine individuals were administered 2 cycles of TL-pulsed DC vaccination, which were comprised of 4 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 DC and activated killer cells from the tissue cultures of tumor-draining lymph nodes in individuals with primary lung cancer. The study subjects received four courses of chemotherapy along with immunotherapy every 2 months for 2 years. The subjects (n=28) 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 DC 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 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 5 had stable disease. The mean survival time was 9.8 months. The authors noted that further randomized controlled studies of large numbers of subjects are needed to confirm the efficacy of this combination adoptive immunotherapy for pancreatic cancer.

Li and colleagues (2012) evaluated the safety and efficacy of autologous cytokine-induced killer (CIK) cell transfusion used in conjunction with gemcitabine and cisplatin (GC) chemotherapy. In their study, 60 individuals treated at one of three cancer centers in China, with nasopharyngeal carcinoma (NPC) and distant metastasis after radiotherapy were randomly divided into two groups with 30 subjects in each group. From September 2007 to August 2008, individuals in the chemotherapy group were treated with GC alone while the other group received CIK cells and GC. As of December 31, 2010, there were 18 deaths in the GC group and 13 deaths in the GC+CIK group. The GC group demonstrated 1- and 2-year OS rates of 83.3% (25/30) and 50% (15/30), respectively, while the GC+CIK group had OS rates of 90% (27/30) and 70% (21/30), respectively. The OS curve plotted with the Kaplan-Meier method demonstrated that the survival rate in the GC+CIK group was higher than that in the GC group within 2 years of follow-up, but the difference was not significant (p=0.137, log-rank test). The progression-free survival (PFS) curve showed that the PFS of GC+CIK group was higher than that of the GC group (p=0.023, log-rank test). The authors concluded that the combination of CIK cells and GC regimen chemotherapy can be used as a potential treatment for those with advanced NPC. Principal limitations of this study included its small size and limited follow-up.

Liu and colleagues (2012) conducted a prospective randomized controlled trial at a single Chinese cancer center to evaluate the effects of autologous CIK cell immunotherapy in individuals with metastatic renal cell carcinoma (RCC). Between June 2005 and June 2008, 148 individuals were randomized to receive either autologous CIK cell immunotherapy (arm 1, n=74), or IL-2 in combination with human interferon (IFN)-alpha-2a (arm 2, n=74). The primary endpoint was OS. The 3-year PFS and OS in arm one were 18% and 61% respectively, as compared with 12% and 23% respectively in arm two (PFS, p=0.031; OS, p<0.001). The authors concluded that CIK cell treatment could improve the prognosis of metastatic RCC. Initial study results are promising and larger multi-center studies will be needed to confirm these early findings.

In 2013, Yang and colleagues performed a paired study comparing the clinical outcomes of advanced non-small cell lung cancer (NSCLC) treated with either chemotherapy only (group 1, n=61) or chemotherapy plus DC-activated CIK cells (group 2, n=61). Of the 122 total subjects, the 1- and 2-year overall survival rates were 37.3 and 10.1% in group 1 (chemotherapy alone) and 57.2 and 27.0% in group 2 (chemotherapy plus DC-activated CIK cells), respectively. Compared to chemotherapy alone, chemotherapy plus DC+CIK cells enhanced the clinical efficacy of chemotherapy for advanced NSCLC subjects (p<0.05). In group 2, 18 subjects with squamous cell carcinoma and 36 subjects with adenocarcinoma were evaluated for survival rate. There were no significant differences in the survival rate between the subjects with adenocarcinoma and squamous cell carcinoma in group 2 (p>0.05). The 1- and 2-year survival rates were 58.3 and 30.9% for adenocarcinoma and 49.2 and 39.4% for squamous carcinoma, respectively. Compared to unstimulated CIK cells, DC-activated CIK cells significantly enhanced antitumor activity in-vitro. The authors stated “the present study suggests that DC + CIK cells have enhanced antitumor effects and chemotherapy plus DC+CIK cells improved the clinical outcomes of conventional chemotherapy for advanced NSCLC patients.” However, they further noted that in the future a larger cohort randomized trial will be needed.

In 2022, Rohaan and colleagues reported the results of a multicenter, open-label trial comparing TIL therapy and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy (ipilimumab). A total of 168 individuals with unresectable stage IIIC or IV melanoma were randomly assigned in a 1:1 ratio to the two therapy groups (n=84 in each group). The majority of subjects (62%) had failed first-line anti-PD-1 therapy. TILs were generated from resected melanoma metastases. PFS was the primary endpoint. Median PFS was 7.2 months in the TIL group and 3.1 months in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; p<0.001). Median OS in the TIL group was 25.8 months (95% CI, 18.2 to not reached) vs. 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. An objective response was observed in 49% of subjects in the TIL group (95% CI, 38 to 60) and 21% in the ipilimumab group (95% CI, 13 to 32). The authors concluded that TIL therapy is superior to CTLA-4 blockade as a second-line treatment in individuals with advanced melanoma. However, treatment-related adverse events were more frequently seen individuals who received TILs (100%) than in those who received ipilimumab (57%). In addition, treatment resistance remains a problem in the majority of individuals treated with TIL therapy, and mechanisms of resistance are not understood.

Chesney and colleagues (2022) also studied the efficacy and safety of a type of TIL therapy (lifileucel) in individuals with advanced melanoma after progression on immune checkpoint inhibitors such as anti-PD-1 therapy. In this multicenter Phase 2 trial, a total of 153 individuals were treated with lifileucel. The primary endpoint was independent review committee-assessed objective response rate (ORR). ORR was 31.4% (95% CI: 24.1% to 39.4%); median OS and PFS were 13.9 and 4.1 months, respectively. At a median study follow-up of 27.6 months, median duration of response was not reached, with 41.7% of the responses maintained for ≥18 months. The authors concluded that treatment with lifileucel TIL cell therapy demonstrated clinically meaningful activity and durability in heavily pretreated patients with advanced melanoma with a high tumor burden. A major limitation of this industry-sponsored study is the single-arm, non-randomized, uncontrolled, non-blinded design that precludes comparative assessment of the observed OS and PFS with those of other treatments.

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, that is, the use of interleukin-2; (2) active specific immunotherapy, for example, immunization with a variety of therapeutic vaccines; (3) passive non-specific immunotherapy, that is, transfer of lymphokine-activated killer cells; and (4) passive specific immunotherapy; that is, 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 (for example, 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.
4. Cytokine-induced killer (CIK) cells: Recently CIK has been recognized as a new type of anti-tumor effector cell, which can proliferate rapidly in vitro, with stronger anti-tumor activity and broader spectrum of targeted tumor than other reported anti-tumor effector cells (LAK and TIL cells). These cytotoxic cells are generated by incubation of peripheral blood monocytes in the presence of various types of cytokines such as CD3 monoclonal antibody, IL-2, IL-1, and interferon-gamma (Hontscha, 2011).

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(5):884-890.
4. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022; 10(12):e005755.
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. 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.
7. 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.
8. Dudley ME, Wunderlich J, Yang JC, 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. 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.
10. Figlin RA, Thompson JA, Bukowski RM, 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.
11. Gardini A, Ercolani G, Riccobon A, 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; 87(1):46-52.
12. Hontscha C, Borck Y, Zhou H, et al. Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol. 2011; 137(2):305-310.
13. 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.
14. Khammari A, Nguyen JM, Leccia MT et al. Tumor infiltrating lymphocytes as adjuvant treatment in stage III melanoma patients with only one invading lymph node after complete resection: results from a multicenter, randomized clinical phase III trial. Cancer Immunol Immunother. 2020; 69(8):1663-1672.
15. 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.
16. 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.
17. Klingemann HG. Cellular therapy: Finishing the job. J Hematother and Stem Cell Res. 2001; 10(4):435-436.
18. Klingemann HG. Cellular therapy of cancer with natural killer cells: will it ever work? J Hematother Stem Cell Res. 2001; 10(1):23-26.
19. Kobari M, Egawa S, Shibuya K, et al. Effect of intraportal adoptive immunotherapy on liver metastases after resection of pancreatic cancer. Br J Surg. 2000; 87(1):43-48.
20. 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.
21. 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.
22. Lee WC, Wang HC, Hung CF, et al. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother. 2005; 28(5):496-504.
23. 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.
24. Li JJ, Gu MF, Pan K, et al. Autologous cytokine-induced killer cell transfusion in combination with gemcitabine plus cisplatin regimen chemotherapy for metastatic nasopharyngeal carcinoma. J Immunother. 2012; 35(2):189-195.
25. Link CJ, Seregina T, Traynor A. Cellular suicide therapy of malignant disease. Stem Cells. 2000; 18(3):220-226.
26. Liu L, Zhang W, Qi X, et al. Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res. 2012 Mar 15; 18(6):1751-1759.
27. 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.
28. Rohaan MW, Borch TH, van den Berg JH, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N Engl J Med. 2022; 387:2113-2125.
29. 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.
30. Santin AD, Bellone 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(2):271-280.
31. Small EJ, Fratesis P, Reese DM, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol. 2000; 18(23):3894-3903.
32. Stift A, Friedl J, Dubsky P, et al. Dendritic cell-based vaccination in solid cancer. J Clin Oncol. 2003; 21(1):135-142.
33. 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.
34. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomized trial. Lancet. 2000; 356(9232):802-807.
35. Thiounn T, Pages F, Medjean A. Adoptive immunotherapy for superficial bladder cancer with autologous macrophage activated killer cells. J Urol. 2002; 168(6):2373-2376.
36. 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; eed17(10):887-900.
37. 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.
38. 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 Neurooncol. 2000; 48(2):113-120.
39. Yang L, Ren B, Li H, et al. Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients. Cancer Immunol Immunother. 2013; 62(1):65-73.
40. 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.
41. Zhang Guo-Qing, Zhao Hong, Wu Jian-Yu, et al. Prolonged overall survival in gastric cancer patients after adoptive immunotherapy. World J Gastroenterol, 2015; 21(9):2777-2785.

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.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 January 18, 2023.

1. American Cancer Society. What is cancer immunotherapy? Revised December 27, 2019. Available at: http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Immunotherapy/immunotherapy-what-is-immunotherapy. Accessed on January 18, 2023.

Adoptive Immunotherapy
Autolymphocyte Therapy
Biotherapy
Cell Therapy
Cytokine-Induced Killer (CIK) Cells
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)