Abstract
2502 Background: Immunotherapy is a promising modality for the treatment of cancer, and elucidating the mechanism of action is crucial to guiding patient selection and developing future immunotherapeutic strategies. Engagement of the immune molecule NKG2D by the cancer antigen MICA is important for immune surveillance of many cancers. Tumors can evade immune surveillance by shedding cell surface MICA, which leads to dampening of anti-tumor immunity. Investigations by our laboratory revealed that patients responding to immunotherapy can mount antibody responses targeting MICA, which permits re-engagement of immunity. Methods: Patients with advanced cancer treated at our institution with immunotherapies (tumor cell vaccination, ipilimumab) were identified, including several with long-term clinical remissions. Plasma was analyzed for MICA reactivity to three distinct MICA alleles, and rare memory B cells reactive to MICA were isolated using tetramerized MICA protein. Immunoglobulin heavy and light chain variable domains were sequenced with single cell RT-PCR to generate recombinant monoclonal antibody. Results: Plasma from patients treated with immunotherapy revealed considerable inter-patient variation in reactivity to MICA. Patients with marked plasma reactivity (including several with sustained clinical remissions) were selected for isolation of rare memory B cells reactive to MICA. From these cells, we have generated a recombinant fully-human MICA-reactive monoclonal antibody that exhibits binding to a variety of MICA alleles. Conclusions: We have developed novel methods to analyze anti-MICA antibody responses and isolate rare memory B cells from cancer patients who gained significant clinical benefit from immunotherapy. This has facilitated the generation of fully human recombinant anti-MICA monoclonal antibody. To our knowledge, this is the first example of a specific antibody reactive to a cancer antigen isolated from a cancer patient responding to immunotherapy. As these antibody responses likely played a role in tumor destruction, these results inform the development of new antibody-based immunotherapies targeting the NKG2D-MICA pathway.
Published Version
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