Mutant KRAS vaccines for pancreatic cancer under clinical development

 

A recent case report demonstrated that adoptive T-cell transfer targeting the KRAS G12D mutation in a metastatic colorectal cancer patient induced tumour regression [1]. This promising result showed in a clinical setting that T cells are capable of targeting and eliminating colon tumour cells expressing KRAS G12D mutant peptides complexed with major histocompatibility complex (MHC) I proteins at their cell surface. It has implications for all cancers with prevalent mutant KRAS expression. In the most common form of pancreatic cancer PDAC, KRAS is mutated in up to 90% of cases.

Two companies Targovax and GlobeImmune are developing vaccines that contain KRAS mutant peptides for patients with pancreatic cancer. These vaccines involve injection of the peptides and subsequent in vivo generation of a T-cell response against the pancreatic cancer. Targovax’s lead RAS vaccine is called TG01. The company reported that the phase I part of a Phase I/II trial of TG01 and gemcitabine for patients with resected adenocarcinoma of the pancreas [2] demonstrated that TG01 induced immune responses in 92% of patients. Interim survival data showed that 14 out of 15 evaluable patients were still alive after one year. Safety and tolerability were demonstrated.

GlobeImmune’s product is clinically more advanced with efficacy shown in a subset of pancreatic pancreatic cancer patients in a phase II clinical trial (see here). A companion MALDI-TOF mass spectrometry diagnostic has been developed to predict which pancreatic cancer patient are most likely to benefit from the vaccine based on their tumours protein expression profile.

As was demonstrated by GlobeImmune’s phase II trial not all pancreatic cancer patients with KRAS mutations are guaranteed to benefit. This is most likely due to pancreatic cancer’s “cold” immunoscore (see here). KRAS vaccine combination strategies with agents that improve pancreatic cancer’s immunoscore will likely increase the number patients who respond to mutant RAS vaccines.

 

Refs

  1. Tran E, Robbins PF, Lu Y-C, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 2016;375:2255-2262. DOI: 10.1056/NEJMoa1609279.
  2. ClinicalTrials.gov Identifier: NCT02261714 – Antigen-specific Cancer Immunotherapy (TG01) and Gemcitabine as Adjuvant Therapy in Resected Pancreatic Cancer.
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