Saurav D. Haldar

Key Points Crbn I391V mice degrade known thalidomide derivative targets and recapitulate thalidomide-induced cytopenias and teratogenicity. Degradation of Ck1α is sufficient to explain the in vivo therapeutic window of lenalidomide in del(5q) myelodysplastic syndrome.

Pancreatic cancer cells are characterized by deregulated metabolic programs that facilitate growth and resistance to oxidative stress. Among these programs, pancreatic cancers preferentially utilize a metabolic pathway through the enzyme aspartate aminotransferase 1 [also known as glutamate oxaloacetate transaminase 1 (GOT1)] to support cellular redox homeostasis. As such, small molecule inhibitors that target GOT1 could serve as starting points for the development of new therapies for pancreatic cancer. We ran a high-throughput screen for inhibitors of GOT1 and identified a small molecule, iGOT1-01, with in vitro GOT1 inhibitor activity. Application in pancreatic cancer cells revealed metabolic and growth inhibitory activity reflecting a promiscuous inhibitory profile. We then performed an in silico docking analysis to study inhibitor–GOT1 interactions with iGOT1-01 analogues that possess improved solubility and potency properties. These results suggested that the GOT1 inhibitor competed for binding to the pyridoxal 5-phosphate (PLP) cofactor site of GOT1. To analyze how the GOT1 inhibitor bound to GOT1, a series of GOT1 mutant enzymes that abolished PLP binding were generated. Application of the mutants in X-ray crystallography and thermal shift assays again suggested but were unable to formally conclude that the GOT1 inhibitor bound to the PLP site. Mutational studies revealed the relationship between PLP binding and the thermal stability of GOT1 while highlighting the essential nature of several residues for GOT1 catalytic activity. Insight into the mode of action of GOT1 inhibitors may provide leads to the development of drugs that target redox balance in pancreatic cancer.

Cancer immunoprevention applies immunologic approaches such as vaccines to prevent, rather than to treat or cure, cancer. Despite limited success in the treatment of advanced disease, the development of cancer vaccines to intercept premalignant states is a promising area of current research. These efforts are supported by the rationale that vaccination in the premalignant setting is less susceptible to mechanisms of immune evasion compared with established cancer. Prophylactic vaccines have already been developed for a minority of cancers mediated by oncogenic viruses (e.g., hepatitis B and human papillomavirus). Extending the use of preventive vaccines to non-virally driven malignancies remains an unmet need to address the rising global burden of cancer. This review provides a broad overview of clinical trials in cancer immunoprevention with an emphasis on emerging vaccine targets and delivery platforms, translational challenges, and future directions.

TPS814 Background: Novel strategies are needed to improve immune responses in “cold” tumors such as pancreatic ductal adenocarcinoma (PDAC) and mismatch repair-proficient colorectal cancer (MMRp CRC). As a frequent oncogenic driver, mutant KRAS (mKRAS) neoantigens are attractive targets to augment anti-tumor immunity in both diseases. Recently, adoptive transfer of mKRAS G12D-specific T cells has shown durable tumor regressions in patients with metastatic CRC and PDAC (Tran et. al., 2020; Leidner et. al., 2022). Furthermore, our preclinical work has demonstrated that combining a mKRAS neoantigen vaccine with immune-modulating agents prevents progression of premalignant lesions to PDAC in mice (Keenan et. al., 2014). Based on this rationale, our study pairs a pooled synthetic long peptide (SLP) mKRAS vaccine with dual checkpoint blockade to assess safety and immunogenicity in patients with resected PDAC and chemorefractory MMRp CRC. Methods: This is a first-in-human, single-arm, open-label phase I trial evaluating a pooled SLP mKRAS vaccine combined with ipilimumab/nivolumab (ipi/nivo) in patients with resected PDAC (Cohort A, n = 12) and MMRp metastatic CRC (Cohort B, n = 12) The vaccine consists of poly-ICLC adjuvant admixed with SLPs corresponding to six common mKRAS subtypes: G12D, G12R, G12V, G12A, G12C, and G13D. In priming phase, the mKRAS vaccine is given on days 1, 8, 15, and 22 along with ipi/nivo. In boost phase, the mKRAS vaccine is given on weeks 13, 21, 29, 37, and 45 along with nivo alone. Cohort A patients who remain disease-free can continue to receive boost vaccines in a 12-month extended treatment phase. Eligible patients must have molecular tumor testing that demonstrates one of the six KRAS mutations listed above. Cohort A patients must be disease-free following completion of adjuvant chemotherapy within 6 months prior to study entry. Cohort B patients must have confirmed MMRp status, exposure to ≥ 2 prior lines of standard chemotherapy, and measurable disease amenable to biopsies at baseline and week 7. The co-primary endpoints of this study are safety and T cell response. Adverse events will be graded per NCI CTCAE v5.0. T cell response will be determined by the maximal percent change in IFNγ-producing mKRAS-specific T cell density within 16 weeks post-vaccination compared to baseline. Secondary endpoints include disease control and objective response rates at 16 weeks per RECIST v1.1/iRECIST (Cohort B only) as well as disease-free/progression-free and overall survival. Correlative studies will examine treatment-associated changes in T cell receptor (TCR) repertoire diversity by next-generation TCR sequencing of peripheral blood and tumor specimens. Patient accrual began in May 2020 and is completed for Cohort A. Enrollment is currently ongoing for Cohort B. Study drug support provided by Bristol Myers Squibb. Clinical trial information: NCT04117087 .