Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies

Abstract

Hereditary cancer syndromes (HCS) account for 5~10% of all cancer diagnosis. Lynch syndrome (LS) is one of the most common HCS, caused by germline mutations in the DNA mismatch repair (MMR) genes. Even with prospective cancer surveillance, LS is associated with up to 50% lifetime risk of colorectal, endometrial, and other cancers. While significant progress has been made in the timely identification of germline pathogenic variant carriers and monitoring and early detection of precancerous lesions, cancer-risk reduction strategies are still centered around endoscopic or surgical removal of neoplastic lesions and susceptible organs. Safe and effective cancer prevention strategies are critically needed to improve the life quality and longevity of LS and other HCS carriers. The era of precision oncology driven by recent technological advances in tumor molecular profiling and a better understanding of genetic risk factors has transformed cancer prevention approaches for at-risk individuals, including LS carriers. MMR deficiency leads to the accumulation of insertion and deletion mutations in microsatellites (MS), which are particularly prone to DNA polymerase slippage during DNA replication. Mutations in coding MS give rise to frameshift peptides (FSP) that are recognized by the immune system as neoantigens. Due to clonal evolution, LS tumors share a set of recurrent and predictable FSP neoantigens in the same and in different LS patients. Cancer vaccines composed of commonly recurring FSP neoantigens selected through prediction algorithms have been clinically evaluated in LS carriers and proven safe and immunogenic. Preclinically analogous FSP vaccines have been shown to elicit FSP-directed immune responses and exert tumor-preventive efficacy in murine models of LS. While the immunopreventive efficacy of “off-the-shelf” vaccines consisting of commonly recurring FSP antigens is currently investigated in LS clinical trials, the feasibility and utility of personalized FSP vaccines with individual HLA-restricted epitopes are being explored for more precise targeting. Here, we discuss recent advances in precision cancer immunoprevention approaches, emerging enabling technologies, research gaps, and implementation barriers toward clinical translation of risk-tailored prevention strategies for LS carriers. We will also discuss the feasibility and practicality of next-generation cancer vaccines that are based on personalized immunogenic epitopes for precision cancer immunoprevention.

Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer

“…The resulting FSPs can serve as neoantigens when they are expressed. Frameshift-neoantigen-based vaccines with different formulations have been tested and showed promising activities clinically and preclinically for cancer prevention and treatment (14,15,(93)(94)(95)(96)(97). In this study, we confirmed that these tumor organoids and intra-cecal implanted tumors expressed characteristic FSMs/FSPs with variable mutation frequency and VAF.…”

Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome

“…Novel treatment regimens need to be explored to balance efficacy while minimizing toxicity to improve the patient’s tolerance to immune-based combinations. Immune surveillance using vaccines targeting tumor neoantigens are in clinical trials in patients with heterozygous MMR-deficient Lynch syndrome following success in preclinical models 28 , 29 , and need to be systematically explored for patients with CMMRD.…”

Lynch Syndrome: From Multidisciplinary Management to Precision Prevention

“…These findings have paved the way for the development of cancer vaccines in both prevention and interception settings. Indeed, in these scenarios, local immunity within the tumor molecular environment (TME) is less compromised, and there remains low clonal heterogeneity of tumor antigens [ 121 ]. A clinical phase I/II trial was conducted in patients with history of or current dMMR CRC to evaluate the safety and immunogenicity of an FSP-based vaccine, utilizing FSP neoantigens derived from mutant AIM2, HT001, and TAF1B.…”