A heterologous vaccine (adenovirus prime, samRNA boost) targeting 20 neoantigens from common KRAS and TP53 mutations was safe when combined with ICB in a phase I trial. Although 88% of patients mounted T cell responses to KRAS neoantigens, the trial ORR was 0%, and 15/19 patients experienced PD. In vitro antigen presentation of KRAS epitopes was minimal, but was rescued by exclusion of TP53 from the vaccine, suggesting immune competition. A KRAS-exclusive vaccine induced stronger KRAS-specific T cell responses in HLA-A*11:01 transgenic mice, motivating the design of a new vaccine containing 4 repeated KRAS antigens.
Contributed by Morgan Janes
ABSTRACT: Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9_months and 7.9_months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .
Author Info: (1) Gritstone bio, Emeryville, CA, USA. (2) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Gritstone bio, Emeryville, CA, USA. (4) Gritstone bio, Emeryville, CA, US
Author Info: (1) Gritstone bio, Emeryville, CA, USA. (2) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Gritstone bio, Emeryville, CA, USA. (4) Gritstone bio, Emeryville, CA, USA. (5) Sarah Cannon Research Institute, Nashville, TN, USA. (6) Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA. (7) University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA. (8) Mayo Clinic, Rochester, MN, USA. (9) University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA. (10) Virginia Cancer Specialists, Fairfax, VA, USA. (11) University of California, Los Angeles, Los Angeles, CA, USA. (12) Gritstone bio, Emeryville, CA, USA. (13) Gritstone bio, Emeryville, CA, USA. (14) Gritstone bio, Emeryville, CA, USA. (15) Gritstone bio, Emeryville, CA, USA. (16) Gritstone bio, Emeryville, CA, USA. (17) Gritstone bio, Emeryville, CA, USA. (18) Gritstone bio, Emeryville, CA, USA. (19) Gritstone bio, Emeryville, CA, USA. (20) Gritstone bio, Emeryville, CA, USA. (21) Gritstone bio, Emeryville, CA, USA. (22) Gritstone bio, Emeryville, CA, USA. (23) Gritstone bio, Emeryville, CA, USA. (24) Gritstone bio, Emeryville, CA, USA. (25) Gritstone bio, Emeryville, CA, USA. (26) Gritstone bio, Emeryville, CA, USA. (27) Gritstone bio, Emeryville, CA, USA. (28) Gritstone bio, Emeryville, CA, USA. (29) Gritstone bio, Emeryville, CA, USA. (30) Gritstone bio, Emeryville, CA, USA. (31) Gritstone bio, Emeryville, CA, USA. (32) Gritstone bio, Emeryville, CA, USA. (33) University of California, Los Angeles, Los Angeles, CA, USA. (34) The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. (35) MD Anderson Cancer Center, Houston, TX, USA. (36) Gritstone bio, Emeryville, CA, USA. (37) Gritstone bio, Emeryville, CA, USA. (38) Gritstone bio, Emeryville, CA, USA. kjooss@gritstone.com.
