Development of targeted therapies for mutant RAS cancers

The development of cancer immunotherapies has revolutionized patient outcomes and survival across a wide range of cancer types, yet there are still a significant number of patients that relapse and develop progressive disease following initial treatment. Mutations in the RAS gene family is known to negatively impact cancer progression and treatment outcomes, and are among the most frequent genetic mutations observed in cancers. However, as RAS mutations are exclusively found in cancer cells they can also be considered novel cancer specific targets for attacking cancer immunologically. Therapies targeting RAS mutations are therefore considered to be highly promising with significant potential for reducing risk of relapse and improving patient outcomes across a range of cancer types. However, few treatment options are currently available and of limited efficacy, highlighting the significant unmet medical need for patients with RAS mutations. Importantly, however, one promising treatment candidate for mutant RAS cancers is Targovax’s TG vaccine technology, which is the result of a substantial body of basic and clinical research at Norwegian hospitals and research institutions. The present project aims to further the clinical development of Targovax’s next generation mutant RAS- targeted immunotherapy platform using innovative treatment combinations and patient selection methods that may further boost treatment efficacy in this population of cancer patients.

Point mutations in the RAS family genes are the most frequently occurring oncogenic driver mutations, and are present in around 30% of all cancers. As such, finding therapies that effectively target these mutations is a high unmet medical need that has been a major focus in both academic and industry oncology R&D for the past three decades. However, due to the structure and localization of the RAS protein the target has remained elusive, and it was only very recently that the first RAS-targeting small molecule drug achieved accelerated approval from the FDA, namely the small molecule inhibitor Sotorasib (Lumakras). Although a very important step forward for the treatment of RAS-mutated cancers, Sotorasib only deals with one specific mutant variant, and has so far only proven effective in lung cancer. In addition, the duration of response appears limited, probably due to tumor escape via alternative RAS mutations. Therefore, there is still significant potential for treatment approaches that can deepen and prolong responses and deal with multiple RAS mutation variants. Targovax´s mutant RAS TG01 vaccine offers exactly such an opportunity, by covering 7 RAS mutations in one product. A vaccination approach also offers the additional advantage of driving endogenous T-cell responses against RAS mutant cells through recognition of MHC-presented RAS mutant neoepitopes, and subsequent lasting immune memory. Indeed, in prior clinical trials with the TG01 vaccine, presence of mutant RAS reactive memory T-cells was detected years after vaccination in several patients. The main objective of the present innovation project is to further the clinical development of Targovax's mutant RAS TG platform by employing novel combination treatment approaches in mutant RAS cancers, as well as taking advantage of advances in biomarker based patient selection to further improve treatment effects and address a population of cancer patients with very high unmet medical needs.