To systematically identify recurrent clonal neoepitopes in treatment-resistant patients, Gumbert and Sagie et al. developed and applied the “Spot Neoantigens in Metastases” (SpotNeoMet) pipeline to metastatic cancer samples from the Hartwig Medical Foundation, using primary tumor samples from TCGA as control. Focusing on the common androgen receptor (AR) H875Y mutation in castration-resistant prostate cancer, they identified three neopeptides and validated their presentation and immunogenicity. Two cloned cognate TCRs were highly specific and led to killing of prostate cancer cells endogenously expressing AR H875Y in vitro and in vivo.
Contributed by Ute Burkhardt
ABSTRACT: New approaches that generate long-lasting therapeutic responses in therapy-resistant metastatic cancer patients are urgently needed. To address this challenge, we developed SpotNeoMet, a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neo-peptides presented by common HLAs. Using HLA-immunopeptidomics, we discovered three novel neopeptides derived from Androgen Receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCRs) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y specific TCRs are highly specific and kill prostate cancer cells presenting AR neo-peptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for mCRPC patients. Moreover, SpotNeoMet offers a systematic route to identify 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers.
Author Info: (1) Weizmann Institute of Science, Rehovot, Israel. (2) Weizmann Institute of Science, Rehovot, Israel. (3) Institute for Research in Biomedicine, Barcelona, Spain. (4) Weizmann In
Author Info: (1) Weizmann Institute of Science, Rehovot, Israel. (2) Weizmann Institute of Science, Rehovot, Israel. (3) Institute for Research in Biomedicine, Barcelona, Spain. (4) Weizmann Institute of Science, Rehovot, Israel. (5) Weizmann Institute of Science, Rehovot, Israel. (6) Institute for Research in Biomedicine, Barcelona, Spain. (7) Princeton University, Princeton, NJ, United States. (8) Vall d'Hebron Institute of Oncology, Spain. (9) Weizmann Institute of Science, Rehovot, Israel. (10) Flatiron Institute, New York, NY, United States. (11) Weizmann Institute of Science, Rehovot, Israel. (12) Weizmann Institute of Science, Israel. (13) Weizmann Institute of Science, Rehovot, Israel. (14) Weizmann Institute of Science, Israel. (15) Weizmann Institute of Science, Rehovot, Israel, Israel. (16) University of Michigan-Ann Arbor, Ann Arbor, United States. (17) University of Michigan-Ann Arbor, Ann Arbor, United States. (18) Vall d'Hebron Institute of Oncology, Barcelona, Barcelona, Spain. (19) Vall d'Hebron Institute of Oncology, Spain. (20) Hadassah Medical Center, Jerusalem, Israel. (21) Weizmann Institute of Science, Israel. (22) Weizmann institute, Rehovot, Israel, Israel. (23) Weizmann Institute of Science, Rehovot, Israel, Israel. (24) Weizmann Institute of Science, Rehovot, Israel. (25) Princeton University, Princeton, NJ, United States. (26) University of British Columbia, Vancouver, British Columbia, Canada. (27) University of British Columbia, Vancouver, British Columbia, Canada. (28) University of Michigan-Ann Arbor, Ann Arbor, MI, United States. (29) University of California, San Francisco, San Francisco, CA, United States. (30) Dana-Farber Cancer Institute, Boston, MA, United States. (31) Weill Cornell Medicine, New York, NY, United States. (32) Vall d'Hebron Institute of Oncology, Barcelona, Spain. (33) Memorial Sloan Kettering Cancer Center, United States. (34) Vall d'Hebron Institute of Oncology, Spain. (35) Institute for Research in Biomedicine, Barcelona, Spain. (36) Weizmann Institute of Science, Rehovot, Israel.
