Adoptive Immunotherapy

POLICY NUMBER

A.8.01.01

DESCRIPTION

The spontaneous regression of certain cancers (i.e., renal cell carcinoma, melanoma) supports the idea that a patient’s immune system can delay tumor progression and, on rare occasions, can eliminate tumors altogether. These observations have led to research into various immunologic therapies designed to stimulate a patient’s own immune system. Adoptive immunotherapy is a method of activating lymphocytesand/or other types of cells for the treatment of cancer and other diseases. Cells are removed from the patient, processed for some period of time, and then infused back into the patient.

Health Disparities in Certain Cancers

Hepatic tumors can arise as primary liver cancer (hepatocellular cancer) or by metastasis to the liver from other tissues. A study from 2016 determined that the incidence of liver cancer was higher among White individuals, Black individuals, and Hispanic individuals born after 1938. The incidence of hepatocellular carcinoma was twice as high for US-born Hispanic men compared to Hispanic men born outside of the US. This may be due to the increased risk of smoking, hepatitis B or C infection, and diabetes among US-born Hispanic individuals.

Based on data from 2016 through 2021, kidney cancer is more common in men than women and occurs more often in non-Hispanic American Indian, Alaskan Native individuals, and non-Hispanic Black individuals compared to individuals of other races or ethnicities. American Indians and Alaska Natives have higher death rates from kidney cancer than any other racial or ethnic group. A cohort study by Howard and colleagues included 158,445 patients with localized kidney cancer from the National Cancer Database between 2010 and 2017. Investigators found that female patients were treated more aggressively compared with male patients, with lower adjusted odds of undertreatment and higher adjusted odds of overtreatment. They also found that Black and Hispanic patients had higher adjusted odds of undertreatment and overtreatment compared to White patients, and uninsured status was associated with lower adjusted odds of overtreatment and higher adjusted odds of undertreatment. These results suggest that sex, race and ethnicity, and socioeconomic status are associated with disparities in guideline-based treatment for localized kidney cancer, specifically, with increased rates of non-guideline based treatment for women and Black and Hispanic patients.

Adoptive Immunotherapy

Adoptive immunotherapy uses "activated" lymphocytes or other immune cells as a treatment modality. Both non-specific and specific lymphocyte activation are used therapeutically. The nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes.

T Lymphocytes and Killer Cells

Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T-cell growth factor interleukin-2 and other cytokines. More recent techniques have yielded select populations ofcytotoxic T lymphocytes with specific reactivity to tumor antigens. Peripheral lymphocytes are propagated in vitro with antigen-presenting dendritic cells that have been pulsed with tumor antigens. Alternatively, innate tumor-infiltrating lymphocytes (TIL) from the tumor biopsy are propagated in vitro with interleukin-2 and anti-CD3 antibody, a T-cell activator. The expansion of TIL for clinical use is labor-intensive and requires laboratory expertise. Only a few cancers are infiltrated by T cells in significant numbers; of these, TIL can be expanded in only approximately 50% of cases. These factors limit the widespread applicability of TIL treatment. Recently, cytokine-induced killer cells have been recognized as a new type of antitumor effector cells, which can proliferate rapidly in vitro, with stronger antitumor activity and a broader spectrum of targeted tumors than other reported antitumor effector cells.

Cellular Therapy and Dendritic Cell Infusions

The major research challenge in adoptive immunotherapy is to develop immune cells with anti-tumor reactivity in quantities sufficient for transfer to tumor-bearing patients. In current trials, two methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions.

Adoptive cellular therapy is “the administration of a patient’s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lymphodepleting preparative regimen.” Protocols vary, but include these common steps:

1. lymphocyte harvesting (either from peripheral blood or from tumor biopsy)

2. propagation of tumor-specific lymphocytes in vitro using various immune modulators

3. selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay

4. lymphodepletion of the host with immunosuppressive agents

5. adoptive transfer (i.e., transfusion) of lymphocytes back into the tumor-bearing host.

Dendritic cell-based immunotherapy uses autologous dendritic cells (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigens in vivo. Autologous dendritic cells harvested from the patient are either pulsed with antigen or transfected with a viral vector bearing a common cancer antigen. The activated ADCs are then re-transfused into the patient, where they present antigen to effector lymphocytes (CD4-positive T-cells, CD8-positive T-cells, and in some cases, B cells). This initiates a cytotoxic response against the antigen and against any cell expressing the antigen. In cancer immunotherapy, ADCs are pulsed with tumor antigens; effector lymphocytes then mount a cytotoxic response against tumor cells expressing these antigens. (See the  Cellular Immunotherapy for Prostate Cancer medical policy for a discussion of dendritic cell-based immunotherapy for prostate cancer.)

In an attempt to regulate the host immune system further, recent protocols use various cytokines (e.g., IL-7 and IL-15 instead of interleukin-2) to propagate lymphocytes. Protocols also differ in the extent of host lymphodepletion induced prior to transfusing lymphocytes to the tumor-bearing host.

There are currently no adoptive immunotherapy products within the scope of this policy that are U.S. Food and Drug Administration (FDA)-approved. In 2022, the primary analysis of the Netherlands Cancer Institute-sponsored phase 3 M14TIL randomized controlled trial (NCT02278887) was published by Rohaan and colleagues. This study, comparing autologous TIL therapy with ipilimumab in patients with advanced cutaneous melanoma who had received no more than 1 prior line of therapy, met its primary endpoint of prolonged progression-free survival in TIL recipients. The TIL product was prepared at a local facility and, to date, has not been reported to be associated with regulatory application submissions.

In 2022, a pooled analysis of cohorts enrolled in the phase 2 C-144-01 trial (NCT02360579) was published by Chesney and colleagues. In this analysis conducted in patients with advanced non-uveal melanoma who had received a median 3 prior lines of therapy, lifileucel, an autologous CD4⁺/CD8⁺ TIL product, demonstrated an overall response rate of 31.4%; with median follow-up of approximately 27 months, median duration of response had not been reached. On the basis of this trial, a Biologics License Application for lifileucel for patients with advanced melanoma was submitted by Iovance Biotherapeutics and accepted by the FDA for priority review, with a Prescription Drug User Fee Act action date of November 25, 2023.

Chimeric antigen receptor T-cell therapies for certain hematologic malignancies (eg, tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel) are discussed separately in the Chimeric Antigen Receptor Therapy for Leukemia and Lymphoma medical policy.

POLICY

All adoptive immunotherapy techniques intended to enhance autoimmune effects are considered investigational for the indications included, but not limited to, cancers associated with Epstein-Barr virus, Cytomegalovirus-associated cancers, nasopharyngeal cancer, renal cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, non-small-cell lung cancer, melanoma, glioblastoma multiforme, medullary thyroid cancer, pancreatic cancer, and cancers treated with autologous peripheral T lymphocytes containing tumor antigen-specific T cell receptors.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

5/1994: Approved by Medical Policy Advisory Committee (MPAC).

8/1998: Reviewed by MPAC; expanded investigational indications.

2/2001: Active Specific Immunotherapy with Therapeutic Melanoma Vaccines reviewed by MPAC; considered investigational.

4/16/2001: Managed Care Requirements deleted.

7/12/2001: MPAC statement 2/2001 added and hyperlink to Active Specific Immunotherapy with Therapeutic Melanoma Vaccines.

2/7/2002: Investigational definition added.

4/18/2002: Type of Service and Place of Service deleted.

3/17/2003: Code Reference section updated.

10/13/2004: Code Reference section reviewed, no changes.

11/7/2005:  Code Reference section updated, ICD9 diagnosis code V58.12 added.

8/17/2007: Policy reviewed, no changes.

12/19/2008: Policy reviewed, policy statement re-written for clarity.

04/23/2010: Policy description and guidelines updated based on new research findings. Policy statement unchanged. Deleted outdated references in the Sources section.

01/19/2012: Policy reviewed; no changes.

04/02/2013: Policy reviewed; no changes.

03/10/2014: Added administration of cytokine-induced killer cells to the policy statement as investigational.

01/23/2015: Policy description updated regarding expansion of tumor-infiltrating lymphocytes for clinical use. Added cytotoxic T-lymphocytes and genetically-engineered T-cells to the investigational policy statement. Added "autologous" to "antigen-loaded autologous dendritic cells" in the investigational policy statement.

08/14/2015: Medical policy revised to add ICD-10 codes. Removed ICD-9 diagnosis code V58.12 from the Code Reference section.

02/12/2016: Policy description updated. First investigational policy statement updated to remove lymphokine-activated killer cells (LAK) from the investigational statement. Investigative definition updated in policy guidelines section.

05/25/2016: Policy number A.8.01.01 added.

02/01/2018: Policy title changed from "Adoptive Immunotherapy" to "Adoptive Immunotherapy, Including Chimeric Antigen Receptor (CAR) T Cell Therapies." Policy description updated to add information regarding tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) and disease processes indicated. Policy statement updated to add medically necessary indications for Kymriah and Yescarta and that prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi is required. Policy Guidelines updated regarding patient selection criteria and treatment administration requirements. Policy Exception added for Federal Employee Program (FEP) and State and School Employee subscribers. Sources section updated. Medically Necessary codes table added.

03/28/2018: Code Reference section updated to add HCPCS code Q2041, effective 04/01/2018.

05/10/2018: Policy statement criteria for Kymriah updated to change "2 or 3" to "3" in the following statement: Patient has active central nervous system 3 acute lymphoblastic leukemia (ie, white blood cell count ≥5 cells/μL in cerebrospinal fluid with presence of lymphoblasts).

10/02/2018: Policy description updated regarding FDA approval of tisagenlecleucel (Kymriah) for the treatment of adults with relapsed or refractory large B-cell lymphoma. Second policy statement updated to add Kymriah. Second policy statement criteria updated to change "prior treatment with Yescarta" to "prior CD19-directed CAR T-cell therapy treatment." Added statement that "Tisagenlecleucel (Kymriah) intravenous infusion is considered investigational for the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma." Policy Guidelines updated to add the recommended dosage for patients with B-cell acute lymphoblastic leukemia and large B-cell lymphoma.

10/31/2018: Policy statement updated to add requirements for designated and approved providers for immunotherapy and gene therapy. Immunotherapy and Gene Therapy must be provided by a Network Provider designated and approved by the Company where the Company has a contract in place with the Network Provider for the specific Immunotherapy and Gene Therapy services. Benefits for Immunotherapy and Gene Therapy are only provided when Medically Necessary and a treatment plan is submitted by the Network Provider and approved by the Company prior to initiation of treatment. Benefits will not be provided for Immunotherapy and Gene Therapy services performed by Non-Network Providers or Network Providers that are not designated and approved by the Company. Benefits for Immunotherapy and Gene Therapy will not be provided if a treatment plan is not submitted by the contracted Network Provider and approved by the Company prior to initiation of treatment.

12/03/2018: Language updated regarding requirements for designated and approved providers for immunotherapy and gene therapy as follows: Benefits for Immunotherapy and Gene Therapy will not be provided unless Medically Necessary subject to Medical Policy and a treatment plan submitted by the Network Provider and approved by the Company prior to the initiation of treatment. Immunotherapy and Gene Therapy services must be received from a Network Provider designated and approved by the Company where the Company has a contract in place with the Network Provider, either directly or through BlueCard®, for the specific Immunotherapy and Gene Therapy service. Intent unchanged.

12/20/2018: Policy Exceptions section updated to add Self-Insured Groups. Code Reference section updated to add new 2019 CPT codes 0537T, 0538T, 0539T, and 0540T. Revised code description for HCPCS code Q2041. Added HCPCS code Q2042, effective 01/01/2019.

03/08/2019: Policy reviewed; no changes.

01/10/2020: Policy description updated regarding chimeric antigen receptor T cell therapy. Policy statements unchanged. Policy Guidelines updated regarding autologous lymphocytes. Sources updated. Code Reference section updated to remove deleted HCPCS code Q2040.

10/07/2020: Code Reference section updated to add new ICD-10 procedure codes 30230C0, 30233C0, 30240C0, and 30243C0, effective 10/01/2020.

02/18/2021: Tecartus approved by Pharmacy & Therapeutics (P&T) Committee. Added Tecartus (brexucabtagene autoleucel) to the top of the policy. Policy description updated to add information regarding chimeric antigen receptor (CAR) T cell therapy, diffuse large b-cell lymphoma (DLBCL), mantle cell lymphoma, and available CAR T cell therapies. Policy statements for acute lymphoblastic leukemia (ALL) and DLBCL updated to include the generic names for Yescarta and Kymriah. For ALL, revised policy criteria to state the following: The member has not previously received CD19-directed CAR T-cell therapy treatment or any other gene therapy as standard medical care/therapy or in a clinical trial setting and is not being considered for treatment with any other gene therapy. For DLBCL, updated policy statement criteria to state the following: The member has adequate organ and bone marrow function with no significant deterioration in organ function expected within 4 weeks after apheresis. Added policy statement criteria for mantle cell lymphoma stating: One treatment course (one dose) per lifetime of Tecartus (brexucabtagene autoleucel) may be considered medically necessary for relapsed or refractory mantle cell lymphoma when ALL of the criteria are met. Added the following policy statements: 1) All CAR-T therapies are considered investigational for all other indications. 2) Services related to delivery and/or administration of a medication which have not been approved through the BCBSMS PA review process will be considered not medically necessary. Policy Exceptions updated. Policy Guidelines updated regarding the recommended target dose of Tecartus and BCBSMS request for medical records. Sources updated. Code Reference section updated to add HCPCS code C9073.

03/30/2021: Code Reference section updated to add new HCPCS Code Q2053, effective 04/01/2021.

07/13/2021: Policy revised to move Chimeric Antigen Receptor Therapy to a separate policy. Policy title changed from "Adoptive Immunotherapy, Including Chimeric Antigen Receptor (CAR) T Cell Therapies" to "Adoptive Immunotherapy." Policy section revised to state that all adoptive immunotherapy techniques intended to enhance autoimmune effects are considered investigational for the indications included, but not limited to, cancers associated with EBV, CMV, nasopharyngeal cancer, renal cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, NSCLC, melanoma, glioblastoma multiforme, medullary thyroid cancer, pancreatic cancer, and cancers treated with autologous peripheral T lymphocytes containing tumor antigen-specific T cell receptors. Policy Exceptions updated. Policy Guidelines updated to remove medically necessary definition. Sources updated. Code Reference section updated to add CPT code 36511 as investigational.

01/17/2022: Policy reviewed; no changes.

12/15/2022: Policy description updated regarding health disparities in certain cancers. Policy statement unchanged.

11/16/2023: Policy description updated regarding products and trials. Policy statement unchanged.

10/22/2024: Policy description updated regarding kidney cancer. Policy statement unchanged.

SOURCE(S)

Blue Cross Blue Shield Association policy #8.01.01

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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