Checkpoint inhibition therapies function by amplifying anti-tumor immune responses that naturally exist in many patients, but fail to benefit patients whose cancers don’t exhibit signs of previous immune recognition. The ascendance of these powerful immunotherapies to the forefront of clinical oncology practices has reinvigorated the drive to develop cancer vaccines for eliciting de novo immune responses against tumors, with the goal of expanding the fraction of patients who benefit from them. However, despite the success of immunizations against infectious diseases, enshrined as some of the greatest achievements in the history of biomedical science, the field of cancer vaccinology has long been plagued by failures to provide clinical efficacy. Setting their sights on improving tumor immunization outcomes, Drs. Steven Fling and Martin (Mac) Cheever, of the Vaccine and Infectious Disease Division and Clinical Research Division at Fred Hutch, respectively, helped coordinate and analyze a cross-nation multicenter trial to evaluate a strategy for enhancing vaccine-induced immune responses. “The study was the brainchild of our colleague Dr. Nina Bhardwaj [Co-Director of the Cancer Immunology Program of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai] and was prompted by the critical need to increase effective cancer antigen-specific immune responses,” said Dr. Fling. Recently published in Nature Cancer, “[this work] revealed a clinical strategy to substantially increase effective vaccine induced immune responses, both T cell and antibody”.
T cells are important effectors of anti-tumor immunity, highlighted by the success of checkpoint inhibition therapy, whose primary function is to unleash suppressed anti-tumor T cell responses. Prior to their deployment against infected or transformed target cells, T cells must first undergo an activation process involving interactions with a specialized class of innate immune cells, called ‘antigen-presenting cells’ (APCs). The failure of cancer vaccines to elicit strong T cell responses has been attributed, in part, to the absence of sufficient APC stimulation. “Antigen presenting cells, such as dendritic cells (DCs), are essential for effective T cell responses,” explained Dr. Fling. “Flt3 [fms-like tyrosine kinase 3] ligand, a growth factor for DCs, was discovered ~27 years ago at Immunex Corp. as a hematopoietic factor essential to regulating DC development and maturation. Clinical trials in the 1990s with Flt3L were negative for efficacy, prior to the realization that activated DCs can present antigens to and activate T cells, but by sharp contrast, non-activated DCs can induce tolerance.” In a multicenter phase II clinical trial, Dr. Fling and colleagues evaluated the efficacy of Flt3L in combination with poly-ICLC, a commonly used vaccine adjuvant that activates DCs, in enhancing immune responses elicited by a DC-targeted tumor vaccine in high-risk remission melanoma patients.
60 patients with resected melanoma were randomized into groups receiving the vaccine alone (consisting of the NY-ESO-1 cancer antigen fused to the DC-targeting antibody, anti-DEC-205, along with the poly-ICLC adjuvant), or receiving Flt3L pre-treatment prior to vaccine administration. The investigators hypothesized that inclusion of Flt3L would expand DCs, leading to increased presentation of the vaccine antigen to T cells and yielding improved immune responses. Serial blood samples were drawn from the patients prior to, during, and after the treatment courses for analysis, with the goal of assessing the impact of the immunization strategy on the response to the NY-ESO-1 antigen, the anti-tumor response characteristics, and the frequencies and phenotypes of immune subsets, including DCs. Both treatment regimens were well tolerated, with few high-grade adverse events.
“The hypothesis proved correct,” said Dr. Fling, “targeting antigen to DC[s] expanded and activated by Flt3L was highly effective.” They observed dramatic expansion and activation of DC subsets following Flt3L administration. Beyond DCs, they also saw increases in other immune cell populations, including monocytes, B cells, natural killer cells, and T cells, indicating broad immune mobilization. Further phenotypic analyses indicated increased signs of activation across many immune cell populations. Honing in on antigen-specific immunity, T cell responses to NY-ESO-1 were more prevalent, arose earlier, and were stronger in magnitude amongst patients receiving Flt3L pre-treatment. Flt3-treated patients also exhibited significantly more robust antibody responses against the vaccine antigen. Finally, the investigators turned to transcriptional profiling of the blood samples to more finely characterize immune responses elicited in each cohort. Overall, patients receiving Flt3L pre-treatment saw much more robust transcriptional changes after vaccination compared to those receiving the vaccine alone, and the expression patterns were indicative of early and durable Flt3L-induced immune responses.
“The study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination and leads to a robust, immunogenic vaccine response,” explained Dr. Fling. “This regimen holds tremendous potential for both cancer and infectious disease vaccine strategies.” This study was not designed or powered to evaluate clinical efficacy of the regimen but, moving forward, Drs. Fling and Cheever and colleagues would like to test the use of Flt3L in combination with other available immunotherapies. “[W]e anticipate that combining this enhanced T cell-stimulating vaccine strategy with the current standard of checkpoint blockade has the potential to significantly improve checkpoint blockade and anti-tumor responses and will help invigorate the cancer vaccine and immunotherapy field.” This work also raised important basic immunology questions, including the roles of different DC subsets in shaping vaccine responses. “The data on expansion of most, but not all, DC subsets needs to be further explored to determine what DC subsets are most associated with the enhanced immune response. Further identification of the DC subsets responsible for inducing the observed high-level immune response might allow development of even more specific and more effective vaccine strategies.”
This work was funded by the National Institutes of Health.
UW/Fred Hutch Cancer Consortium members Chihiro Morishima, Mary Disis, and Mac Cheever contributed to this work.
Nina Bhardwaj, Philip A. Friedlander, Anna C. Pavlick, Marc S. Ernstoff, Brian R. Gastman, Brent A. Hanks, Brendan D. Curti, Mark R. Albertini, Jason J. Luke, Ana B. Blazquez, Sreekumar Balan, Davide Bedognetti, Joseph M. Beechem, Andrea S. Crocker, Leonard D’Amico, Patrick Danaher, Thomas A. Davis, Thomas Hawthorne, Bruce W. Hess, Tibor Keler, Lisa Lundgren, Chihiro Morishima, Nirasha Ramchurren, Darawan Rinchai, Andres M. Salazar, Bob A. Salim, Elad Sharon, Laura A. Vitale, Ena Wang, Sarah Warren, Michael J. Yellin, Mary L. Disis, Martin A. Cheever & Steven P. Fling. Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets. Nat Cancer 1, 1204–1217 (2020). https://doi.org/10.1038/s43018-020-00143-y