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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.
Adoptive immunotherapy uses "activated" lymphocytes as a treatment of modality. Both non-specific and specific lymphocyte activation are used therapeutically. Non-specific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy (ALT), increases the number of activated lymphocytes. Initially, this was done by harvesting peripheral lymphokine-activated killer (LAK) 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 tumor than other reported antitumor effector cells.
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 (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 lymphodepleting preparative regimen.” Protocols vary, but include these common steps:
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 transfused back 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 (e.g., IL-7 and IL-15 instead of IL-2) to propagate lymphocytes. Protocols also differ in the extent of host lymphodepletion induced prior to transfusing lymphocytes to the tumor-bearing host.
Note: Allogeneic stem-cell transplantation following nonmyeloablative conditioning of the recipient (known as reduced-intensity conditioning or RIC) may also be referred to as “adoptive immunotherapy” in the literature. However, RIC stem-cell transplantation relies on a donor-versus-malignancy effect of donor lymphocytes. In contrast, the adoptive immunotherapy techniques described in this policy enhance autoimmune effects primarily. The use of RIC in stem-cell transplantation is discussed for specific cancers in individual policies related to stem-cell transplantation.
Adoptive immunotherapy is not a U.S. Food and Drug Administration (FDA)-regulated procedure.
Related medical policy -
POLICYAdoptive immunotherapy, using adoptive cellular therapy (ACT) for the administration of cytotoxic T-lymphocytes, cytokine-induced killer cells, tumor-infiltrating lymphocytes (TIL), antigen-loaded autologous dendritic cells (ADCs), or genetically-engineered T-cells is considered investigational.
Other applications of adoptive immunotherapy are considered investigational.
POLICY GUIDELINESAutologous lymphocytes used as part of adoptive immunotherapy may be harvested in a pheresis procedure, or may be isolated from resected tumor tissue.
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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY5/1994: 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 rearch 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.
SOURCE(S)Blue Cross Blue Shield Association policy #8.01.01
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.