Immunotherapy

Immunotherapy for cancer is best thought of as part of a broader subject, namely biologic therapy, or the application of biologic-response modifiers (BRMs). These agents can act through one or more mechanisms (1) to stimulate the host's antitumor response by increasing the number of effector cells or by producing one or more soluble mediators (eg, lymphokines); (2) to decrease host-suppressor mechanisms; (3) to alter tumor cells to increase their immunogenicity or make them more susceptible to damage by immunologic processes; and (4) to improve the host's tolerance to cytotoxic drugs or radiotherapy (eg, by stimulating bone marrow function with granulocyte colony-stimulating factor or other hematopoietic factors). The first three mechanisms represent manipulation of immunologic processes and are considered immunotherapy. A given BRM may have immunologic and nonimmunologic effects; eg, IFN-α- enhances the expression of TAA on tumor cells and increases NK cell activity, but it also inhibits tumor cell proliferation directly through nonimmunologic mechanisms.

Passive Cellular Immunotherapy

Passive cellular immunotherapy is a term used when activated, specific effector cells are directly infused into a patient and are not induced or expanded within the patient. Early attempts involve reinfusion of the patient's lymphocytes after expansion in vitro by exposure to IL-2 (T-cell growth factor). These cells are termed lymphokine-activated killer cells (LAK cells). Sometimes the cells are first exposed to phytohemagglutinin, a lymphocyte mitogen, to expand a broad variety of peripheral lymphoid cells. Such approaches are an extension of work in which allogeneic lymphocytes were cross-transfused between tumor patients after attempted immunization with tumor grafts. The availability of purified recombinant IL-2 in large quantities has made the LAK cell plus IL-2 technique feasible, and some melanoma and renal carcinoma patients have shown objective responses.

Because infusion of IL-2 after LAK cell infusions is associated with significant toxicity, variations of these methods are under study. One approach is to isolate and expand populations of lymphocytes that have infiltrated tumors in vivo and thus may have tumor specificity (termed tumor-infiltrating lymphocytes [TILs]). Infusion of TILs permits use of lower levels of IL-2 with equal or greater antitumor effects. TILs can also be genetically modified to express tumoricidal molecules to increase their cytotoxicity.