Researchers recently used next-generation sequencing data to describe the landscape of neoantigens in 184 patients with multiple myeloma (MM) and successfully validated the use of neoantigen-specific T cells in patients with MM. The study, which was published in Clinical Cancer Research, is the first to experimentally determine which neoantigens have the ability to provoke the immune system into recognizing and killing cancer cells in patients with MM.1

The investigation included 92 patients with relapsed/refractory MM who had relapsed following at least 5 lines of therapy, including autologous stem cell transplantation (ASCT). The researchers extracted DNA and RNA from sorted CD138+ cells from bone marrow aspirates. The team found shared neoantigens in 3 MM oncogenic driver genes (KRAS, NRAS, and IRF4) across multiple patients. Furthermore, they validated “a mutation-derived neoantigen-specific T-cell recognition and activation associated with clinical response in MM.”1

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Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York, noted that tumor neoantigens represent excellent targets for immunotherapy because of their specific expression in cancer tissue. Until now, he explained in an interview with Hematology Advisor, there has been no direct evidence that DNA mutations induce neoantigen-specific T-cell responses following immunotherapy in MM.

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Hans Lee, MD, of MD Anderson Cancer Center in Houston, Texas, commented this is an important study because it shows proof of concept that neoantigens can be identified through next-generation sequencing in tumor samples from patients with myeloma. Even more importantly, the study demonstrated immunogenic T-cell responses and clonal expansion can be linked to some of these specific neoantigens in patients with myeloma responding to immunotherapeutic approaches.

“This study provides a strong preclinical rationale for pursuing personalized neoantigen vaccine approaches that can be manufactured based on an individual patient’s tumor mutation profile,” Dr Lee told Hematology Advisor. “Personalized neoantigen vaccine approaches may be particularly attractive due to low toxicity in myeloma precursor states such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma, as is being investigated in an ongoing study at MD Anderson Cancer Center ( Identifier: NCT03631043).”

He added that these pilot clinical studies will need to demonstrate that neoantigen vaccines can elicit immunogenic responses and, more importantly, demonstrate efficacy with acceptable toxicity.

In terms of future applications of this vaccine, Sandip Patel, MD, of the University of California San Diego, and deputy director of the San Diego Center for Precision Immunotherapy, said a vaccine approach could potentially be effective against refractory disease but could also be a useful method of cancer interception to prevent the transformation of more indolent disease such as MGUS or smoldering myeloma into MM.