Adoptive immunotherapy is a method of activating lymphocytes for the treatment of cancer and other diseases.
Adoptive immunotherapy uses “activated” lymphocytes as a treatment 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 yield select populations of 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, 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. Cytokine-induced killer (CIK) cells have recently been recognized as a new type of anti-tumor effector cells, which can proliferate rapidly in vitro, with stronger anti-tumor activity and broader spectrum of targeted tumor than other reported anti-tumor effector cells. (1)
The spontaneous regression of certain cancers, such as renal cell cancer or melanoma, supports the idea that a patient’s immune system can delay tumor progression and, on rare occasions, can eliminate the tumor altogether. These observations led to research interest in a variety of immunologic therapies designed to stimulate a patient’s own immune system. 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.” (2) 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) 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. 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 the lymphocytes to the tumor-bearing host.
Autologous lymphocytes used as part of adoptive immunotherapy may be harvested in a pheresis procedure or may be isolated from resected tumor tissue.