Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer

Abstract

BackgroundOncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial.MethodsAdult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring.ResultsThirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+T cells on treatment.ConclusionPexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.Trial registration numberNCT03206073.

Combined immune checkpoint inhibition with durvalumab and tremelimumab with and without radiofrequency ablation in patients with advanced biliary tract carcinoma

“…The normalized data was further analyzed using Gene Set Variation Analysis (GSVA) 41 . Furthermore, CIBERSORTx was performed to estimate the proportion of immune cells in a bulk sample as previously described 36 . The TPM gene expression matrix output by RSEM was reformatted to include only gene symbols.…”

“…34,35 2.4.1 | Bulk RNA-seq and data analysis RNA was extracted from fresh-frozen needle biopsy tumor samples at baseline and post-treatment as previously described. 36 Libraries were prepared using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina, using the 100 or 5 ng protocols based on RNA availability at the CCR Sequencing Facility. Samples with <5 ng RNA ("low concentration") were prepared using the 5 ng protocol.…”

“…41 Furthermore, CIBERSORTx was performed to estimate the proportion of immune cells in a bulk sample as previously described. 36 The TPM gene expression matrix output by RSEM was reformatted to include only gene symbols. Immune infiltration was profiled using CIBERSORTx 34 with the LM22 signature matrix in absolute mode with batch correction.…”

VB-111 (ofranergene obadenovec) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single center, single arm, phase II trial

“…Gating strategies were performed as previously described. 22 The populations from either live, CD45+leukocytes (for immune profiling) or live, CD3+lymphocytes (for T-cell profiling) were then down sampled and exported as .csv files. After import of these .csv files, graph-based clustering and UMAPs (or Uniform Manifold Approximation and Projection) were generated using the Partek Flow software pipeline (Build V.10.0.22.0703, Partek, St. Louis, Missouri, USA).…”

Redefining the battle against colorectal cancer: a comprehensive review of emerging immunotherapies and their clinical efficacy

“…The combined treatment with PexaVec, durvalumab, and tremelimumab exhibited promising clinical efficacy in individuals with pMMR mCRC. However, additional investigations are required to ascertain the corresponding predictive biomarkers ( 37 ). Another study showed that the combination of bevacizumab and FOLFOX with durvalumab, a PD-L1 inhibitor, and oleclumab, an anti-CD73 mAb, modestly improved response rates but did not confer any PFS advantage over standard-of-care treatment alone ( 200 ).…”