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Date Printed: June 26, 2017: 01:24 AM

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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

01-96400-01

Original Effective Date: 12/15/02

Reviewed: 04/27/17

Revised: 05/15/17

Subject: Adoptive Immunotherapy

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Position Statement Billing/Coding Reimbursement Program Exceptions Definitions Related Guidelines
           
Other References Updates    
           

DESCRIPTION:

The spontaneous regression of certain cancers (eg, 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 lymphocytes and/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.

Studies of cytotoxic T lymphocytes, lymphokine-activated killer cells (LAK), tumor-infiltrating lymphocytes (TIL), autologous dendritic cells, cytokine-induced killer cells, and genetically engineered T cells suggest that some adoptive immunotherapies may improve outcomes in some cancer types. However, the impact of adoptive immunotherapy on patient outcomes (eg, increased survival, improved quality of life) has yet to be clarified in large randomized clinical trials (RCTs). Specifically, high-quality RCTs with adequate follow-up are needed to show that there is a significant survival advantage for adoptive immunotherapy.

Adoptive immunotherapy uses “activated” lymphocytes as a treatment modality. Both nonspecific and specific lymphocyte activation are used therapeutically. Nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes. Initially, this was done by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T-cell growth factor interleukin-2 (IL-2) and other cytokines. More recent techniques have yielded select populations of cytotoxic 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 IL-2 and anti-CD3 antibody, a T-cell activator. 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.

The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing patients. In current trials, 2 methods are studied: adoptive cellular therapy (ACT) and antigen-loaded dendritic cell infusions.

ACT is “the administration of a patient’s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lympho-depleting 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 ELISA

4. Lympho-depletion of the host with immunosuppressive agents

5. Adoptive transfer (ie, 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. ADCs 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 retransfused into the patient, where they present antigen to effector lymphocytes (CD4+ T cells, CD8+ 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.

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

Genetically engineered T cell immunotherapy uses gene transfer of tumor antigen-specific T-cell receptors (TCR), or synthetic chimeric antigen receptors (CAR). CAR therapy generates T cells that express artificial TCRs that bind tumor cell surface antigens but do not need to match the patient’s immune type. CAR therapy is in a preliminary stage of development.

POSITION STATEMENT:

Adoptive immunotherapy, using adoptive cellular therapy for the administration of lymphokine-activated killer cells (LAK), cytotoxic T lymphocytes, cytokine-induced killer cells, tumor-infiltrating lymphocytes (TIL), antigen-loaded autologous dendritic cells (ADC), or genetically engineered T cells is considered experimental or investigational. The evidence is insufficient to determine the effects of the technology on health outcomes.

BILLING/CODING INFORMATION:

The following code is used to describe adoptive immunotherapy:

HCPCS Coding

S2107

Adoptive immunotherapy, i.e., development of specific anti-tumor reactivity (e.g., tumor infiltrating lymphocyte therapy) per course of treatment (investigational)

NOTE: Providers sometimes report adoptive immunotherapy using CPT procedure codes 36511 and 37799.

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage products: The following Local Coverage Determination (LCD) was reviewed on the last guideline reviewed date: Noncovered Services (L33777), located at fcso.com.

DEFINITIONS:

No guideline-specific definitions apply.

RELATED GUIDELINES:

None applicable.

OTHER:

Other index terms for adoptive immunotherapy:

Note: The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Antigen loaded dendritic cells
Autolymphocyte therapy
CAR T-cell therapy
Chimeric antigen receptor therapy
Cytokine-induced killer cells
Cytotoxic T lymphocytes
Dendritic cells, adoptive immunotherapy
Genetically engineered T cells
Immunotherapy, adoptive
Lymphokine activated killer cells
Tumor infiltrating lymphocytes

REFERENCES:

  1. American Cancer Society News Center. New Immunotherapy Shows Promise Against Melanoma. (09/20/02).
  2. American Society of Clinical Oncology. Adoptive Immunotherapy for Malignant Disease test. Bishop, Michael R and Fowler, Daniel H. (2003).
  3. Blue Cross Blue Shield Association Medical Policy Reference Manual. Adoptive Immunotherapy. 8.01.01 (December 2015).
  4. Blue Cross Blue Shield Association TEC Assessment “Adoptive Immunotherapy for Advanced Renal Cell Carcinoma” (03/94) – Tab 1.
  5. Blue Cross Blue Shield of Florida Technology Assessment “Autolymphocytic Therapy (ALT) for Metastatic Renal Carcinoma” (07/91).
  6. Chen S, et al. A hybrid of B and T lymphoblastic cell line could potentially substitute dendritic cells to efficiently expand out Her-2/neu-specific cytotoxic T lymphocytes from advanced breast cancer patients in vitro. J Hematol Oncol. 2017 Feb 28;10(1):63.
  7. ClinicalTrials.gov.NCT01995344: TIL Therapy in Metastatic Melanoma and IL2 Dose Assessment (METILDA). National Institute for Health Research, United Kingdom. November 2013.
  8. ClinicalTrials.gov. NCT02202928: Adoptive Cell Therapy Plus Chemotherapy and Radiation After Surgery in Treating Patients With Colorectal Cancer. Shenzhen Hornetcorn Bio-technology Company, LTD. July 2014.
  9. Dreno B, Nguyen JM, Khammari A, Pandolfino MC, Tessier MH, Bercegeay S, Cassidanius A, Lemarre P, Billaudel S, Labarriere N, Jotereau F. “Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma.” Cancer Immunol Immunother. 2002 Nov; 51(10): 539-46. Epub 2002 Sep 19.
  10. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL, Schwartzentruber DJ, Hwu P, Marincola FM, Sherry R, Leitman SF, Rosenberg SA. “Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma.” J Immunother. 2001 Jul-Aug; 24(4): 363-73.
  11. ECRI “Technology Update: Interleukin 2 (IL-2) for the Treatment of Renal Cell Carcinoma” (10/97).
  12. ECRI Executive Briefings “Interleukin-2 for the Treatment of Renal Cell Carcinoma” (08/94); “Technology Update: Interleukin 2 (IL-2) for the Treatment of Renal Cell Carcinoma” (10/97).
  13. First Coast Service Options (FCSO) Medicare. Local Coverage Determination (LCD) Noncovered Services (L33777) (10/01/15).
  14. HAYES Brief. “Provenge┬« (Dendreon Corp.) Vaccine for Treatment of Prostate Cancer”. (11/14/05; updated 12/23/07).
  15. HAYES Medical Technology Directory “Active Specific Immunotherapy with Therapeutic Melanoma Vaccines” 06/14/06, updated 07/26/08).
  16. HAYES Medical Technology Directory “Interleukin-2 Therapy for Renal Cell Carcinoma” (INTE0701 – 10/98, archived).
  17. Labarriere N, Pandolfino MC, Gervois N, Khammari A, Tessier MH, Dreno B, Jotereau F. “Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients.” Cancer Immunol Immunother. 2002 Nov; 51(10): 532-8. Epub 2002 Sep 18.
  18. Mosińska P, et al. Dual Functional Capability of Dendritic Cells - Cytokine-Induced Killer Cells in Improving Side Effects of Colorectal Cancer Therapy. Front Pharmacol. 2017 Mar 14;8:126.
  19. Serganova I, et al. Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade. Mol Ther Oncolytics. 2016 Dec 14;4:41-54.
  20. Shapero MH, Kundu SK, Engleman E, Laus R, van Schooten WC, Merigan TC. “In vivo persistence of donor cells following adoptive transfer of allogeneic dendritic cells in HIV-infected patients.” Cell Transplant. 2000 May-Jun; 9(3): 307-17.
  21. Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol. 2017 Feb 21;10(1):53.
  22. Ye B, et al. Genetically Modified T-Cell-Based Adoptive Immunotherapy in Hematological Malignancies. J Immunol Res. 2017;2017:5210459.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Medical Policy & Coverage Committee on 04/27/17.

GUIDELINE UPDATE INFORMATION:

12/15/02

Medical Coverage Guideline Reviewed, Revised, & Reformatted.

11/15/03

Reviewed; no change in coverage statement.

10/15/04

Scheduled review; no change in coverage statement.

11/15/05

Scheduled review; no change in coverage statement; updated references.

11/15/06

Scheduled review; no change in coverage statement; updated references.

09/15/07

Reviewed; reformatted guideline; updated references.

11/15/08

Scheduled review; no change in position statement; updated references.

10/15/09

Scheduled review; position statement unchanged; updated references.

05/11/14

Revision: Program Exceptions section updated.

05/15/17

Scheduled review. Revised description section and position statement section (added coverage [E/I] for cytotoxic T lymphocytes, cytokine-induced killer cells, and genetically engineered T cells). Revised programs exceptions section and index terms. Updated references.

Date Printed: June 26, 2017: 01:24 AM