Trial of a Personalized and Adaptive Neoantigen Dose-Adjusted Vaccine Concurrently With Pembrolizumab

Subjects will be offered clinical trial participation if per RECIST 1.1 they are determined to have stable disease, mixed response, oligoprogressive state (defined as disease progression at a limited number of anatomic sites, with continued response or stable disease at other sites) or non-threatening progressive disease (defined as progression that fits a clinical pattern where the treating physician believes that PD-1 therapy post-progression is appropriate (e.g. multiple sub-centimeter nodules that do not compromise the bronchus)) to an anti-PD-1 or anti-PD-L1 therapy. Eligible subjects will initiate or continue pembrolizumab monotherapy and will have archival tissue and a buccal swab sample (matched normal sample genomic DNA) collected. Whole exome and single cell sequencing studies will be performed using the archival tumor and matched normal sample to identify tumor specific mutations and predict personalized human leukocyte antigen (HLA) binding proteins. Based on this information, 6 neoantigens will be selected for inclusion in the primary personalized vaccine. The primary therapeutic neoantigen vaccine product (PANDA-VAC) will be comprised of 6 peptides at a dose of 300 micrograms (µg) per peptide admixed with local adjuvant Poly-ICLC. PANDA-VAC will be administered subcutaneously to six subjects after their first protocol-mandated disease assessment on pembrolizumab monotherapy. The subjects will receive five priming doses and two booster vaccinations of PANDA-VAC in combination with continued pembrolizumab treatment. Enrollment of the first 3 subjects to receive PANDA-VAC will be staggered by 4 weeks to monitor for acute and subacute adverse events. Subjects with partial response, stable disease, mixed response, oligoprogressive state or non-threatening progressive disease (in the opinion of the treating physician) following the full series of vaccinations may receive adapted vaccine adjusted to address neoantigens emerging during initial PANDA-VAC and pembrolizumab combination therapy. Subjects will have tissue collected for DNA and RNA sequencing and prediction of HLA binding proteins, as delineated above for the initial vaccine production. The therapeutic neoantigen vaccine product will be comprised of up to 2 additional peptides at a dose of 300 μg per peptide (up to 8 total peptides). Peptides targeting neoantigens no longer represented in sequencing data may no longer be included in the neoantigen vaccine product. The primary endpoint of this trial aims to evaluate the safety of the vaccination administered concurrently with pembrolizumab therapy, by estimating the unacceptable toxicity rate.

As generation of either the primary therapeutic or adapted neoantigen vaccine requires: (1) whole exome sequencing studies of the tumor and a matched normal sample from a buccal swab pre-treatment; (2) RNA sequencing of the tumor pre-treatment; and (3) whole exome sequencing of circulating cell-free DNA and DNA derived from circulating tumor cells, information gained from these analyses will also provide extensive exploratory data. With this data, we will study relationships of mutational and genes expression profiles with depth of response to therapy. The purpose of these studies is to generate initial data that will allow us to estimate effect size and variance of the change in immune features with therapeutic neoantigen vaccine treatment in order to design prospective correlative studies in future trials.