In this project, we will continue to study the use of monoclonal antibodies (mAb) against ganglioside antigens as treatment for cancer. We will focus on two gangliosides: GD3 in patients with melanoma, and GD2 in patients with small cell lung cancer (SCLC). Gangliosides GD2 and GD3 have been selected as targets for several reasons. GD3 is abundantly expressed on virtually all melanomas and GD2 is expressed on SCLC. MAbR24 against GD3 has potent immune effector functions including activation of complement and mediation of antibody-dependent cellular cytotoxicity. MAb to gangliosides can also directly inhibit melanoma adhesion and proliferation. Previous studies, by us and by others, have demonstrated objective tumor regression in melanoma patients treated with mouse mAb against GD3 or GD2, Finally, mAb against GD3 have been found to activate T cells; this effect is markedly augmented by low concentrations of interleukin-2. This project will explore three different approaches using mAb to target ganglioside tumor antigens: passive immunization, delivery of cytotoxic doses of radiation, and active immunization against GD3 using an anti-idiotypic mAb.
The specific aims of this project are: 1) Determine whether passive immunization with humanized versions of mAbR24 against GD3 can be used to maintain long-term levels of antibody in patients with melanoma. 2) Test whether cytokines can be used to expand and activate effector cell populations involved in mAbR24 anti-tumor effect. For this specific aim, clinical trials will be carried out combining mAbR24 with interleukin-2 (to expand and activate NK cells and T cells) and with tumor necrosis factor-alpha (to activate neutrophils). 3) Determine whether 131/I-labeled humanized mAb3F8 against GD2 can localize to SCLC tumor sites and result in objective anti-tumor responses. 4) Develop optimal conditions for immunizing melanoma patients against GD3 ganglioside using anti-idiotypic mAbBEC2 which mimics GD3. Conditions to be tested in a series of clinical trials will include: addition of the immune adjuvant QS21, alteration of the BEC2 molecule to enhance the immunogenicity of the variable domains, conjugation of carrier molecules with strong T cell epitopes, and immunization of patients with GD3 ganglioside after priming with the BEC2 vaccine. Once optimized, the vaccine will be tested in patients with measurable disease to determine whether objective tumor regressions can be observed.
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