Dr Fox on a Dark Matter–Containing Multivalent Vaccine in Head and Neck Cancer

Bernard A. Fox, PhD, member, Harder Family Endowed Chair in Cancer Research, Molecular and Tumor Immunology Laboratory, Earle A. Chiles Research Institute, Providence Cancer Institute, discusses insights on the investigation of an off-the-shelf multivalent vaccine that contains cancer’s dark matter, DPV-001, combined with anti–PD-1 and anti-GITR antibodies in patients with head and neck cancer.

Over the past 15 years, Fox says investigator focus has been dedicated to validating findings from a series of clinical trials indicating the development of an autophagosome vaccine derived from 1 sarcoma that could potentially offer cross-protection against 8 out of 9 different sarcomas. Although this outcome might not initially appear remarkable, historical research spanning 50 years had repeatedly demonstrated that sarcomas induced by a chemical carcinogen akin to cigarette smoke exhibit cancerous characteristics mirroring specific cell lines, albeit with distinct hotspot mutations eliciting unique T-cell responses specific to each sarcoma, Fox reports. Upon using the vaccine, investigators observed this remarkable cross-protection, initially attributing it to the transient nature of short-lived proteins, he explains.

However, recent breakthroughs have unveiled a plethora of noncanonical proteins associated with malignant traits that are being expressed, translated, and integrated into a select group of proteins or micropeptides, which then present themselves on the cancerous cell surfaces, Fox expands. A pivotal discovery found that these peptides fail to provoke an immune response, unveiling what can be termed as cancer’s “dark matter,” he says. The reason for this newfound revelation emerging only recently stems from the ongoing pursuit, spanning more than 20 years, to identify targets for anticancer immunity, Fox notes.

The conventional approach involved examining tumor-reactive tumor infiltrating lymphocyte (TIL) cultures from human cases, he expands, saying that researchers employed ctDNA libraries derived from these TIL cultures, integrating them into target cells expressing the HLA molecule, and used the TIL to identify which antigens were being recognized and responded to. This methodological strategy has led to a deeper understanding of the complexity underlying cancer immunity and has laid the groundwork for recent discoveries illuminating the enigmatic components of cancer’s molecular landscape, Fox concludes.