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Adoptive T cell therapy for cancer using Mutant KRAS-specific T cell receptors for T cell engineering

We have isolated, cloned, and characterized multiple T cell receptors (TCRs) from human donors specific for common mutations in KRAS and restricted to highly prevalent HLA types. These TCRs, protected by a Penn provisional filing, are suitable for T cell engineering for the adoptive immunotherapy of cancer patients of select HLA types and tumors expressing particular KRAS mutantions.

The comprehensive bioinformatics, biochemical and immunological assessment of these TCRs is in press (Bear et al, Nature Communications).

Problem:

Mutations of the KRAS gene (mKRAS) serve as the driving oncogene in multiple cancers including lung cancer, colon cancer, and up to 95% of pancreatic ductal carcinoma.
KRAS inhibitors have garnered FDA approval, proving the value of KRAS as a cancer target.
However, there is no approach to target KRAS immunologically.

Solution:

We have shown that peptides derived from mKRAS are expressed on HLA molecules on the surface of tumor cells and can be recognized by cytotoxic T cells, leading to tumor death in vitro and in vivo.
We have isolated mKRAS-specific TCRs and demonstrated that their engineered re-expression confers mKRAS-specific killing ability.
Mutant KRAS specific T cells and TCRs do not recognize wildtype KRAS, addressing a major limitation of CART/TCR efforts for which the target is often expressed in normal tissue.

Technology Overview:

Using blood samples form healthy donors and cancer patients, the team has devised a platform to identify and isolate TCR sequences that bind to peptide-HLA class I complexes with high specificity and potency for mKRAS.
Based on this knowledge, the team has developed a novel mKRAS cancer vaccine (currently being tested in an actively enrolling clinical trial) and has also advanced the data set needed to file an IND for mKRAS TCR-based adoptive T cell clinical trial.
In addition, knowledge of these immunogenic peptide-HLA complexes has driven the development of novel laboratory tools useful for discovery and patient assessment, such as reporter cell lines and dextramers.
The platform and approach is deployable for isolating TCRs specific for other mutated oncogenes, beyond KRAS