Immunotherapy

IMMUNOTHERAPY

The beginning of immunotherapy dates back more than 100 years when it was observed that intratumoral application of bacteria was associated with a strong inflammatory response and, at times, regression of neoplastic lesions. For quite some time, some clinical investigators attempted a type of nonspecific immunotherapy based on the administration of inactivated/attenuated bacteria. The favorite formulation became known as the complete Freund adjuvant, made of attenuated tuberculosis bacilli (bacille Calmette-Guérin, or BCG) mixed with mineral oil (incomplete Freund adjuvant). This formulation, generally administered intradermally or subcutaneously, was effective at eliciting a strong delayed-type hypersensitivity (DTH) response; however, the same formulation is often toxic since it can produce local necrosis and ulcerations.

In an attempt to generate a response that was specific for each tumor, cell-based vac-cines became objects of intense study. Tumor vaccines can be autologous (made of the pa-tient’s own tumor cells) or allogeneic (made of a mixture of tumor cells not from the pa-tient). At least in principle, autologous tumor cell vaccines are specific but available only in limited amount, while allogeneic vaccines can be produced in large quantities, but are not as patient-specific. Allogeneic vaccines are generally made of several established cell lines with the objective of encompassing a wide variety of antigenic specificities for each particular tumor type. Cell-based cancer vaccines appear to be more effective when com-bined with BCG or complete Freund adjuvant, strongly suggesting that the antigenic speci-ficity of the vaccine and the adjuvant effect might work together to enhance the immuno-genicity of the antigens associated with the tumor cells.

We now understand that the problem of translating our knowledge of tumor im-munology into effective immunotherapy centers on the need to provide appropriate and long-lasting co-stimulatory help at the site of tumor growth in order to accomplish and sus-tain effective antitumor response.

It is not the purpose of this review to discuss the many current immunotherapeutic modalities being tested in ongoing clinical studies. Time will tell which approaches will be-come accepted clinical practice because of their relative success. Rather, it may be more relevant to discuss current trends in cancer immunotherapy.

As previously mentioned, IL-2 is now approved for treatment of metastatic melanoma and renal cell cancer. Numerous attempts are being tested in the clinic to in-crease the therapeutic efficacy of IL-2 by combining it with specific antigenic complexes as discussed below.

Tumor vaccines have been the object of numerous trials to determine the feasibility of stimulating the antitumoral immune response by active immunization with a variety of anti-gens, ranging from killed tumor cells to purified tumor antigens. In the most recent studies, synthetic antigenic epitopes (peptides) specific for certain types of cancer are being formu-lated with incomplete Freund’s adjuvant and given in combination with IL-2. The obvious goal of these protocols is to stimulate the host immune response to recognize those tumor-associated antigenic complexes and subsequently promote the destruction of autologous tu-mor cells. The role of IL-2 is to stimulate proliferation and activation of helper and cytotoxic T cells. The administration of these therapeutic synthetic vaccines is repeated several times during each treatment protocol to help establish a sustained anticancer immune response.

An alternative approach to increase the efficiency of tumor vaccines has been to engineer tumor cells to express and release GM-CSF. This approach attempts to activate the host antitumor response at the site of injection by recruiting APCs to the site of vaccine injection, where the expression of tumor-associated antigens may be optimal, as if the ther-apeutic vaccine were a “school” to “educate” the immune response to recognize and sub-sequently kill autologous tumor cells located at other sites in the body. Histological analy-sis of metastatic lesions in many patients enrolled in these experimental studies has confirmed the general validity of this approach, since numerous lesions are heavily infil-trated by lymphocytes and often have extensive areas of hemorrhagic necrosis.

Another approach to increase the immunogenicity of a tumor is called heterogeniza-tion, which can be achieved in a variety of ways, including infecting tumor cells with avirus, transfecting tumor cells with foreign MHC class I or II molecules, or fusing tumor cells with various allogeneic cells. The purpose of heterogenization is to force the host im-mune response to recognize tumor-associated antigens in the context of allogeneic MHC class I or II molecules or in proximity to strong foreign antigens. The allogeneic/foreign antigen would provide a strong co-stimulatory signal to affect an anti-tumor response.

More recently, autologous dendritic cells have been expanded ex vivo from cancer patients or normal volunteers and pulsed with appropriate tumor-specific antigenic epi-topes before reinfusion into the patient. What all these different approaches have in com-mon is to confer immunogenicity to autologous tumor-associated antigens in order to stim-ulate an immune response that may bring measurable clinical benefits.

A totally different approach to tumor immunotherapy is to use monoclonal antibod-ies. Some of the antibodies used in tumor immunotherapy are specific for molecular struc-tures generally expressed on the cell surface of certain tumors (e.g., HER-2 in breast can-cer, anti-CD20 in B-cell lymphomas). Others are equivalent to anti-idiotypic antibodies, which represent surrogate antigens since they bear the internal image of a tumor antigen. The mechanism of action of these antibodies is not entirely clear, because antibody-induced tumor regressions sometimes occur weeks after treatment, suggesting that antibody-medi-ated tumor lysis may not be the only effector mechanism.