New type of Cellular immunotherapy against solid tumours

Scientists have developed a new kind of T-Cell Receptor immunotherapy to treat solid tumours normally seen in pancreatic cancer. 

Every cell has a set of proto-oncogenes which play a role in regulating cell cycle and division. These proto-oncogenes get mutated to form oncogenes which are responsible for driving the formation of malignant tumours. Cells under normal conditions undergo cell death (apoptosis) to maintain homeostasis. Since oncogenes are mutated they can get translated into truncated proteins or enzymes with altered functions, they enable the cells to bypass this process and lead to uncontrolled cell division. Oncogenes work by upregulating the cell proliferation functions of other normal genes.

Along with proto-oncogenes, there are tumor suppressor genes that are present in the cells. In non-mutated states, tumor suppressor genes can suppress the activity of oncogenes. However, in most kinds of cancers both the proto-oncogenes and tumour suppressor genes are mutated, thereby leading to uncontrolled cell division. Many targeted cancer therapies aim to inhibit the oncogenes and upregulate the tumour suppressor genes. 

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Enzymes that are responsible for the transportation of GTP (an energy molecule like ATP) across the nuclear membrane are called RAS GTPases. There are three of these RAS genes in humans- KRAS, NRAS, and HRAS, all of which are proto-oncogenes. RAS mutations account for around 20% of all human malignancies. The vast majority of RAS genomic alterations occur due to missense mutations at codon positions G12, G13, or Q61 that involve the RAS protein GTP-binding domain. This results in the activation of downstream effector cell proliferation enzymes leading to unnatural cell growth and tumour formation. 

Cancers in which KRAS mutations are most common are pancreatic ductal adenocarcinomas, lung adenocarcinomas, and colorectal carcinomas all of which have solid tumours. Over 75% of amino acid substitutions in these cancers occur at the G12 codon position, hence can serve as an ideal drug target. However, no small molecule inhibitors of G12 variants have been successfully developed aside from KRAS G12C that has only recently demonstrated clinical promise. 

Somatic gene mutations within cancer cells may be translated into truncated peptides which are then presented on the surface of tumor cells and serve as foreign epitopes, or neoantigens. These neoantigens may be recognized by T cells of the host immune system and can serve as a possible target for antitumor treatment. Neoantigen-specific T cells can be isolated from the peripheral blood or tumor tissue of antigen-exposed cancer patients, induced by neoantigen vaccination, and can be synthesized in vitro utilizing the various naive T-cell receptor (TCR) from healthy donors. These observations have garnered interest in the development of neoantigen targeted cancer vaccines and adoptive T cell therapies.

A team of scientists at the University of Pennsylvania Health System (Penn Medicine) identified some of the neoantigens that are associated with the KRAS mutations using a multiomics approach. The results of the study were published in Nature Communications. Based on this knowledge, the researchers tested a TCR therapy directed toward KRAS G12 mutations present in conjunction with specific surface neoantigen types highly prevalent among cancer patients. They showed that the TCR therapy led to tumor eradication and prolonged survival in a mouse xenograft model of metastatic lung cancer. 

Neoantigen-based treatment strategies are highly personalized as somatic tumor mutations are rarely the same among patients. However, the high frequency and conserved mutational profile of KRAS provides a unique opportunity to develop a more generalised neoantigen-targeted therapy. mKRAS-specific T cells can be isolated and characterized from the peripheral blood of patients with mKRAS epithelial cancers and can be induced in vaccinated HLA-transgenic mice. These specific T-cells can then serve as a therapeutic agent in order to treat solid tumours present in the types of cancer mentioned previously.

The preclinical work has laid the foundation for the first-in-human clinical trial which is now in the planning stages for the treatment of advanced pancreatic cancer in patients whose tumors harbor specific KRAS mutations. The research further supports the use of neoantigens for targeting tumor cells, for both cellular therapy and cancer vaccines, which have been underway at Penn Medicine and in other places. The first clinical trial for the TCR therapy is projected to launch as soon as 2022, depending on regulatory approval. The study opens the door for researchers to understand the role of the neoantigens derived from the mutated KRAS gene and other mutated oncogenes which aid in driving cancer. 

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