b'With the success of mRNA vaccines for COVID-19, interestthe efficacy of targeted therapies; and 2) identifying variants in is growing for mRNA as a vector for antigens that will initiateindividual genomes to determine their likelihood to respond to a cancer-killing immune response. mRNA cancer vaccinesspecific targeted therapies. offer several advantages over other vaccine platformsMonoclonal antibody (mAb)-based inhibitors of programmed including high potency, safe administration, rapid developmentdeath ligands (PD-L) are one class of targeted therapy that has potential, and cost-effective manufacturing. However, mRNAshown remarkable antitumor activity in a variety of cancers. vaccine applications can also be limited by instability, innateHowever, some patients, even with high levels of PD-L1 antigen, immunogenicity, and inefficient in vivo delivery [13]. Positivedo not respond to currently available mAb therapies. Park et al. results from research studies are fueling continued investigation.demonstrated that natural killer (NK) cell variants can elicit For example, Li et al. identified a CpG oligodeoxynucleotide thatdifferent immune responses in cells with high PD-L1. They used works in combination with an mRNA-based vaccine to boostPCR and Sanger sequencing to genotype NK cells from a variety immune response against melanoma tumors. The investigatorsof human cancer and healthy cell lines, revealing a specific used RT-qPCR to measure induction of the immune responsegenotype that induced an antibody-dependent cytotoxicity based on increased expression of multiple cytokine genes. Theresponse. The authors conclude that combining NK cell therapy combined approach provided stronger antitumor effect thanwith anti-PD-L1 mAbs offers a valuable immunotherapeutic either component alone [14]. strategy for certain cancer profiles [16]. Building genetic insights for cancer therapeuticsChimeric antigen receptor T (CAR T) cell therapy is another Heterogeneous cancers are characterized by diverse molecularstrategy that has shown promising clinical results for some alterations and multiple clinical profiles. Genetic tools that cancancers, but it also faces challenges. Using animal models detect and investigate cancer mutations may yield insights intofor CAR T cell therapy in humans can cause cross-species therapeutic success or resistance, contribute to identification ofreactivity, so animal models are unlikely to be reliable indicators new therapy targets, and ultimately support development of moreof response. In particular, on-target off-tumor behavior of CAR T personalized treatment strategies. cells can result in severe adverse events in patients who express the target antigen on both tumor and healthy tissue. Because Targeted cancer therapy research CARs are highly specific for human antigens, on-target off-tumor Mutations in genetic targets for cancer therapy usually result intoxicity is difficult to predict in current animal models [17,18]. either loss of function (LOF) and accumulation of dysfunctionalCastellarin et al. developed a mouse model that uses high-proteins in tumors, or oncogenic gain of function (GOF) effectsthroughput TaqMan Assays with qPCR to enable tuning of such as tumor proliferation, metastasis, and drug resistance.human HER2 expression levels and can be used to test on-target Precise molecular and genetic profiling to identify relevantoff-tumor toxicity of CAR T cells. The authors concluded that mutations in tumor cells is gaining interest as a source ofthis model is an effective preclinical tool to improve prediction of potential opportunities for targeted treatment options [15].safety and efficacy of CAR T cell therapies [18].Development of targeted cancer therapies faces two primary genetic challenges: 1) identifying mutations that can influence Contents 11'