Target Identification for Passive Immunotherapy in Primary Effusion Lymphoma: Taking a BiTE out of Cancer

Abstract:

Viruses are notorious for their ability to infect their host and surpass host immune systems. Although the human immunological system is advanced and many viral infections last for only a short period of time, there are certain viral invaders that are difficult to clear. Oncoviruses are a rare form of virus that not only remain latent in their host cell, but can drive malignancies. Typically, the human immune system employs cytotoxic T lymphocytes (CTLs) to kill cancerous cells. However, many cancers occupy a tumor microenvironment that coerces nearby regulatory T (T_R_E_G) cells to suppress CTL activation by engaging PD1/PD-L1 signaling pathways. Recent studies have continued to shed light on the novel cancer immunotherapy approaches. One particularly promising immunotherapeutic technique involves the bioengineering of bi-specific T-cell engagers (BiTEs) to create passive immunotherapy solutions personalized to a patients specific mutant allele. Kaposi sarcoma herpesvirus (KSHV) is an oncovirus known to cause primary effusion lymphoma (PEL). There are characteristic somatic mutations in individuals diagnosed with PEL after KSHV infection. Point mutations resulting in missense consequences comprising a new cysteine residue provides an opportunity to test sulfhydryl-reacting covalent chemotherapeuticals. For example, sotorasib and ARS1620 are both able to covalent adduct and inhibit K-Ras G12C alleles. Over time, chemotherapeutical efficacy in patients is reduced as tumors accumulate mutations that bypass K-Ras G12C to reactivate mitosis. We datamined The Cancer Genome Atlas for PEL-enriched point mutations that yielded new cysteine residues in the mutant peptide. As BiTE therapy relies extensively on MHC-I display systems, we filtered out all alleles in which their gene products contained transmembrane domains, and kept only genes that exhibited cytosolic or nuclear subcellular localization, and thus access to the proteasome processing required by MHC-I antigen display. Our work reveals 73 suitable alleles across 59 genes that might serve as candidates in synthetic derivative chemistry involving either ARS1620 or sotorasib. Topological data analysis will allow us to see each candidate gene in multidimensional space to determine the best targets for PEL treatment design.