Weizmann Institute Identifies Immunotherapy Targets in Drug-Resistant Prostate Cancer

Researchers from Israel’s Weizmann Institute of Science have unveiled a promising immunotherapy strategy that targets drug-resistant cancers by exploiting the very genetic mutations responsible for treatment failure.
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The approach centers on a computational tool called SpotNeoMet, which scans large patient datasets to identify recurrent resistance mutations that generate neo-antigens, unique protein fragments displayed exclusively on cancer cells. These neo-antigens trigger immune responses capable of selectively destroying resistant tumor cells while sparing healthy tissue.
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Initial validation focused on metastatic castration-resistant prostate cancer, where most patients eventually develop resistance to hormone therapies. SpotNeoMet pinpointed the androgen receptor H875Y mutation, common in about 7% of these cases, which produces three highly immunogenic neo-peptides. T-cell receptors isolated from healthy donor blood recognized and killed prostate cancer cells presenting these neo-antigens in laboratory and mouse models.
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Unlike personalized therapies requiring weeks of custom manufacturing for each patient, this method enables “off-the-shelf” production from donor cells, potentially available within days after confirming the mutation via tumor sequencing. The strategy identified seven such resistance mutations overall, suggesting a platform expandable to other shared vulnerabilities across patient populations.
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Note: collaborators including Vall d’Hebron Institute in Spain, Princeton University, University of Michigan, Hadassah Medical Center, Sheba Medical Center, University of British Columbia, Dana-Farber Cancer Institute, Weill Cornell Medicine, UCSF, and Memorial Sloan Kettering contributed to the multi-institutional effort published in Cancer Discovery.
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While preclinical, the findings challenge the traditional view of resistance as an insurmountable barrier, positioning it instead as a targetable weakness. Further studies will determine the path to human trials, potentially transforming treatment for prostate cancer and other resistant malignancies within 3-5 years.

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