KRAS is the most frequently mutated driver oncogene, which occurs early in the transformation from a normal healthy to a cancer cell and is found in up to 30% of all cancers. Lead candidate TG01 is a polyvalent mutant RAS neoantigen vaccine designed to elicit immune responses against the seven most frequent mutations in the RAS gene family.

Mutant KRAS Clinical Development

A phase 1/2 clinical trial, with two arms,  (1) 19 patients in the 1st cohort and (2) 13 patients in the 2nd cohort, showed encouraging results of TG01 in combination with gemcitabine to treat patients with surgically resected pancreatic cancer.

A total of 94% of patients (30/32) demonstrated mutant RAS-specific immune activation, and combining the results from the two cohorts, median overall survival (mOS) for all 32 patients was 33.3 months. Encouraging median disease free survival (mDFS) for the full 32 patient sample of 16.1 months, and 19.5 months for the 2nd patient cohort who received the optimized dosing regimen was observed. 72% of patients were still alive two years after surgery, and 38% were still alive three years after surgery.

Next generation KRAS vaccines

Circio is now developing a next generation KRAS vaccines in combination with the adjuvant QS-21 STIMULON. QS-21 STIMULON is a purified, natural saponin proprietary to Agenus.  It has been widely studied and is a critical component of multiple vaccines, including the approved Shingrix® shingles vaccine, and the world’s first malaria vaccine Mosquirix™. There are currently two phase 1/2 clinical studies in progress with leading academic partners.

Pancreatic Cancer

Pancreatic cancer is the third leading cause of cancer-related deaths with less than 10% 5-year survival from diagnosis. As such, there is a major unmet medical need for novel, effective agents to improve outcomes for pancreatic cancer patients.

Mutations in the KRAS genes are found in over 90% of pancreatic cancers, and therefore represent a particularly attractive target in this disease. Targovax´s RAS immunotherapy TG01 targets the  common RAS mutations observed in pancreatic cancer and has previously demonstrated promising immune responses and survival benefit after surgery in a phase 1/2 trial.

A study led by gastrointestinal cancer expert Dr. Anup Kasi at the University of Kansas Cancer Center is testing TG01 vaccination adjuvanted by QS-21 STIMULON™ as monotherapy and in combination with PD-1 CPI balstilimab. TG01 vaccination +/- balstilimab will be tested in 24 pancreatic cancer patients (12 in each arm) who have detectable disease by circulating tumor DNA analysis of blood samples following surgery and SoC. The aim is to evaluate whether mutant RAS T-cell responses generated by TG01, and further boosted by QS-21 STIMULON and balstilimab, may have the potential to eliminate remaining cancer cells to prolong time to relapse and extend patient survival.

Multiple Myeloma

A study led by Dr. Fredrik Schjesvold at Oslo University Hospital is testing TG01 vaccination as a monotherapy in 20 KRAS or NRAS mutated Multiple Myeloma patients who continue to have measurable disease after completion of SoC treatment or have high risk smoldering multiple myeloma. The aim is to assess whether anti-RAS T-cell priming induced by TG01 can enhance the clinical response.