By Marilynn Larkin
NEW YORK (Reuters Health) - 23/4/2019
A series of mouse experiments by Dr. Joshua Brody of the Icahn School of Medicine at Mount Sinai in New York City and colleagues laid the groundwork for the vaccine, enabling them to induce antitumor immunity in vivo.
Specifically, they determined that Fms-like tyrosine kinase 3 ligand (Flt3L) recruits intratumoral dendritic cells, which then can be loaded with tumor-associated antigens and sensitized to a toll-like receptor agonist (TLRa) via radiotherapy (XRT).
Taken together, the Flt3L/XRT/TLRa triplet functions as an ISV, inducing systemic antitumor immunity and adaptive resistance, according to their Nature Medicine report, online April 8.
"Flt3L recruits dendritic cells to the tumor, radiotherapy loads those cells with tumor antigens, and the TLR agonist activates the antigen-loaded dendritic cells, which then seek out any tumor cells bearing those antigens and destroy them," Dr. Brody explained in an email to Reuters Health.
The preclinical studies also demonstrated that adding PD1-blockade to the ISV increased the durable remission rate in the mouse model from ~40% to ~80%.
The findings led to the small phase I ISV trial, still underway (https://clinicaltrials.gov/ct2/show/NCT01976585). As of the writing of the Nature Medicine report, 11 patients with INHL had received multiple doses of Flt3L and TLRa, including injections directly into the tumor. Overall, the ISV was well tolerated. One patient experienced grade 2 fever; all other adverse events were grade 1. Eight patients had partial or complete regression of the treated tumor.
Exploratory analyses showed that at distant (untreated) tumors, two patients progressed, six had stable disease or minor (<50%) regressions lasting 3-18 months. Three patients showed significant distant regressions and achieved remission (one complete response and two partial responses of bulky disease).
"We showed that we could inject two immune stimulants into a single tumor and - by tricking the immune system into thinking that the cancer is like an infection - immune cells were able to traffic throughout the body and eliminate cancer cells wherever they were hiding," Dr. Brody said. "We were surprised by how effective this approach could be in some of our patients with advanced- stage cancer with high tumor burden."
As of now, there is no way to determine which patients might respond to the treatment, Dr Brody acknowledged. "For our newer iteration of this trial, in which we combine the vaccine with 'standard' immunotherapy (anti-PD1 antibodies) (https://clinicaltrials.gov/ct2/show/NCT03789097), we suspect that the common biomarker of amount of PD-L1 expression by the tumor cells may be a predictor of who will have the best responses."
The follow-up trial is enrolling patients with lymphoma, breast cancer, and head/neck cancer, he added.
Dr. Mark Mulligan, Director of the NYU Langone Vaccine Center in New York City, called the approach "promising."
"This study has identified an approach in mice and a small number of humans to activate anti-tumor killer T cells that target indolent non-Hodgkin's lymphomas, and holds out the possibility to add immunotherapy to enhance the anti-tumor effect even more, by taking the 'brakes off' those killer T cells (ongoing human work)," he told Reuters Health by email.
That said, he added, "This is a mouse study and a report of an early phase human trial - the earliest phase, testing the safety of the approach in a relatively small number of subjects, and beginning to collect data on effectiveness. The results need to be confirmed in a larger, randomized, controlled clinical trial of the safety and efficacy of this approach."
Research support was provided by Merck & Co., Celldex Therapeutics, Oncovir and Genentech. Dr. Brody has received funding from Genetech. Two authors are employees of Celldex and one is employed by Oncovir.
Nat Med 2019.