Abstract B14: Neoantigen burden associates with chemoresponse in muscle-invasive bladder cancer patients receiving neoadjuvant chemotherapy
Authors: Abbosh Philip H. , Liu David , Johnson Michael H. , El-Deiry Wafik S. , Plimack Elizabeth R. , Rosenberg Jonathan E. , Allen Eliezer M. Van 
Published: January 2017

Background: The basis of response to chemotherapy is incompletely characterized. The immune system is increasingly recognized as both a key player in cancer control and as druggable target. We hypothesized that the immune system impacts pathologic response in patients undergoing cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive (≥pT2) bladder cancer though neoantigens present in tumors.

Methods: Whole exome sequencing (WES) was performed on tumor DNA from patients in two independent cohorts who underwent cisplatin-based NAC. Pathologic response was defined in the cystectomy specimen. The Memorial Sloan Kettering/Dana Farber Cancer institute (MSKCC/DFCI) cohort (n=50; 25 ≤ pTis responders) and Philadelphia cohorts (n=48; 20 ≤ pTis responders) were treated with gemcitabine/ cisplatin or methotrexate/ vinblastine/ doxorubicin/ cisplatin. Mutation analysis was performed using standard analytical pipelines. Macrohistocompatibility complex (MHC)-restricted neoantigens were identified with netMHCpan and PolySolver. Wilcoxon rank sum test was used to test for significance and all tests were two-sided.

Results: In both cohorts, mutation rate associated with pathologic response (p&lt;0.01 and p&lt;0.001 in Philadelphia and MSKCC/DFCI cohorts, respectively). In the MSKCC/DFCI cohort, the median predicted high affinity (Kd&lt;500 nM) neoantigen count was 311 versus 154 for responding and nonresponding tumors, respectively (p=0.002). For the Philadelphia cohort, the median neoantigen count was 439 versus 218 for responding and nonresponding tumors, respectively (p=8.2 x 10-7). The relationship between neoantigen density and response maintained significance independent of the definition of response (pT0, ≤ pTis, ≤ pT1) and independent of the neoantigen Kd (500 nM, 100 nM, 50 nM) in both cohorts and when cohorts were combined.

Conclusions: Mutational load and neoantigen burden correlate strongly with pathologic response to NAC. Chemotherapy may therefore exert tumor cell autonomous effects through apoptotic mechanisms and a tumor cell extrinsic effect by alerting the immune system via neoantigen presentation on dying cells. Mutation rate is likely directly correlated to neoantigen burden and both may impact patient selection for chemotherapy alone or in combination with immunotherapy agents, and development of antitumor vaccines. Experiments are underway to more directly characterize the impact of the immune system in the response to chemotherapy.

Citation Format: Philip H. Abbosh, David Liu, Michael H. Johnson, Wafik S. El-Deiry, Elizabeth R. Plimack, Jonathan E. Rosenberg, Eliezer M. Van Allen. Neoantigen burden associates with chemoresponse in muscle-invasive bladder cancer patients receiving neoadjuvant chemotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B14.