This in-depth description of a Phase 1 clinical trial initiated in April 2020 provides strong initial evidence for the safety and efficacy of a therapeutic vaccine against fibrolamellar carcinoma (FLC). The vaccine was given in combination with two immune checkpoint inhibitors (ICIs) already approved for use against many cancers. Published in the prestigious journal Nature Medicine on November 24th, the report comes from a team of 28 physicians and scientists at the Johns Hopkins University School of Medicine (Baltimore, MD), St. Jude Children’s Research Hospital (Memphis, TN), and the Fibrolamellar Cancer Foundation (FCF). Drs. Marina Baretti (Johns Hopkins) and Allison Kirk (St. Jude) are co-first authors, and the study was jointly supervised by Drs. Mark Yarchoan (Johns Hopkins) and Paul Thomas (St. Jude).
The vaccine was created to train the immune system to recognize and attack cells that carry the specific genetic change that causes FLC. This genetic change produces an abnormal “fusion” protein, called DNAJ-PKAc or “DP,” that is found only in FLC cancer cells and not in any normal healthy cells. Because nearly every FLC tumor has this exact same fusion protein, the scientists designed an “off-the-shelf” vaccine using a small, lab-made peptide containing the junction point between the two fused proteins. When given to patients, this peptide is intended to trigger the immune system to expand an “army” of trained T cells—immune cells that can specifically recognize and attack any cell displaying the DP fusion protein. In this way, the vaccine aims to target cancer cells while leaving healthy cells unharmed.
Analysis of the first 12 evaluable patients in the study showed that 9 (75%) mounted a strong immune response to the vaccine. Most of the patients whose immune systems reacted to the vaccine experienced meaningful clinical benefit — at minimum, their disease stopped growing or spreading for a period of time. Even more encouraging, half of all patients had long-lasting control of their cancer, and three of them (25%) had major tumor shrinkage, with most of their FLC tumor disappearing. Two of these strong responders elected to discontinue the immune treatment early because the small amounts of residual tumor could be removed surgically. The third, a 13-year-old, completed two years of therapy, and the tumors continued to respond. Today, three to five years after beginning the vaccine treatment for advanced FLC, all three of these patients appear free of active cancer. According to the lead investigators, some of the more recent participants in the trial also have had dramatic clinical responses and currently appear cancer-free.
Surprisingly, analyses of the immune responses mounted by the vaccinated patients revealed that the T cells recognizing the DP fusion were of a type usually labeled as immune “helpers”, rather than “killers.” Exactly how these cells cause FLC tumor cells to die remains to be determined. However, the team succeeding in identifying specific T cell receptors (TCRs) through which these cells recognize target cells containing the fusion junction. This finding opens the door to a next generation therapy in which T cells taken from a new patient could be genetically engineered to make a TCR already proven to be highly effective for recognizing and killing FLC cancer cells. The modified cells would then be expanded to large numbers in a laboratory and infused back into the patient. This type of treatment is known as adoptive cell therapy or TCR-T therapy. Because TCR-T therapy requires the TCR donor and the patient to share certain genetic features—similar to organ transplantation—a small collection of excellent DP-specific TCRs should be enough to make this therapy feasible for a large percentage of patients with FLC.
The study also revealed that in two of the patients, initially strong immune responses to the FLC tumors weakened over time. This appeared to result from “exhaustion” of T cells, rather than loss of the “addiction” of FLC cells to the DP protein for their survival and malignancy, which would likely require the activation of a new cancer driver. These observations highlight the importance of overcoming additional inhibitory factors in the tumor environment, beyond the known immune checkpoints which can be neutralized by ICIs, that may limit the ability of anti-cancer T cells to wipe out their targets. DRP-104, a drug that inhibits glutamine metabolism by FLC cells, is being considered for such conditioning of the tumor microenvironment. That drug is currently being tested in FLC patients in another study funded by FCF.
Whatever improvements await down the road, the fundamental implication of this study is that a significant subset of FLC patients experienced major clinical responses and remain free of detectable cancer after completion of immune therapy that specifically targets the driver of the disease. The study provides a compelling example of the potential value of an off-the-shelf vaccine of a single neoantigen presented by a cancer-driving fusion protein, rather than personalized vaccines targeting neoantigens arising randomly in genetically unstable cancer cells.
The full publication can be accessed here.
Note: This study was partially funded by a grant from FCF.