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Taylor B. Poston, Ph.D., M.P.H.
Most tumors do not respond to T-cell based immunotherapies, but the explanation for this phenomenon has been unclear. Researchers have speculated that there could be insufficient priming of anti-tumor T cells, or if T cells are primed, they are unable to recognize and eradicate the tumor. Recent work in mice and humans by Mount Sinai oncologist Joshua Brody and his research team has helped address this question in the hopes of developing better cancer treatments. They used an in-situ vaccination (ISV) approach that involved local administration of immunostimulatory reagents directly into the tumor to generate systemic anti-tumor CD8 T cell immunity.
This ISV approach combined three distinct parts: Fms-like tyrosine kinase 3 ligand (Flt3L), radiation therapy, and a Toll-like receptor 3 agonist (poly-ICLC). Flt3L is a cytokine that mobilizes dendritic cells (DCs), which are responsible for capturing tumor-associated antigen (TAA) for presentation to T cells. This antigen presentation leads to priming and activation of cytotoxic CD8 T cells that can directly recognize antigen-expressing cancer cells for destruction. However, before DCs can present tumor antigen to ‘educate’ the cytotoxic T cells, the DCs must first become activated and acquire the TAA. This is the purpose of the combined radiation and poly-ICLC approach. After Flt3L injection in mice, local tumor irradiation led to intratumoral inflammation and the release of TAA from dying lymphoma cells that was subsequently taken up and presented by Flt3L-recruited DCs. Following radiotherapy, injections of poly-ICLC synergized with inflammatory mediators released by the irradiated cancer cells and enhanced dendritic cell activation and antigen presentation.
The researchers next confirmed that ISV led to long-term regression of lymphoma tumors that required dendritic cell mediated priming of CD8 T cells capable of infiltrating and recognizing the tumor. However, the tumors recurred within 4 weeks of ISV, which prompted the investigators to assess if cancer cells were upregulating surface molecules that allowed it to evade immune recognition by CD8 T cells. They observed increased expression of Programmed death-ligand 1 (PD-L1) on both the tumor cells and intratumoral dendritic cells. This surface molecule plays a role in suppressing anti-tumor immunity by ligating the Programmed cell death-1 receptor (PD1) on T cells to render them inactive. These results suggested that the PD1/PD-L1 pathway was involved in limiting the anti-tumor effect of ISV. Fortunately, monoclonal antibody therapies that block the PD1/PD-L1 interaction, known as checkpoint inhibitors, have been extensively studied in cancer treatment. By blocking this immune checkpoint, anti-tumor T cells are not repressed and are able to continually target cancer cells. Thus, Brody and colleagues decided to use this approach in combination with ISV. The combination therapy increased durable remissions from ~40% to ~80% of mice and illustrated that all four immunotherapy components (Flt3L, radiation therapy, poly-ICLC, and anti-PD1 antibody) were necessary for optimal anti-tumor effects.
These striking preclinical results in mice led to a clinical trial to treat patients with advanced indolent non-Hodgkin’s lymphoma. 11 patients received nine daily injections of Flt3L into a single target lesion, then two doses of radiotherapy to the same lesions and eight intratumoral injections of poly-ICLC. Results in humans mirrored the previous preclinical findings in the mouse model. Dendritic cells were recruited to the tumor site, and activated CD8 T cells were detected in the blood post-vaccination. Eight patients had partial or complete regression of the treated tumor, and three patients had distant, untreated tumors reduced. One patient had a complete response lasting more than four years, and a patient with a partial response is still in remission six months after ISV. Researchers speculated that induction of PD1-expressing CD8 T cells in ISV-treated patients, particularly non-responders, might benefit from PD1 blockade, as they observed in the pre-clinical model. Clinical trials incorporating anti-PD1 antibodies in combination with ISV are currently ongoing.
These findings could have important clinical implications. ISV has minimal systemic side effects and can be combined with other therapies like checkpoint blockade. The combination of different checkpoint inhibitors has shown efficacy in clinical trials, but are also increasingly toxic. By using ISV to increase DCs at the tumor site that can prime tumor-specific T cells, the efficacy of checkpoint blockade can be enhanced to produce superior anti-tumor immunity, and side effects are reduced by giving patients a lower dose of additional immunotherapies. These combination strategies may be the key to raising survival rates in patients with solid tumors.
Hammerich L, Marron TU, Upadhyay R, Svensson-Arvelund J, Dhainaut M, Hussein S, et al. Nature Medicine. 2019; 25:814-824.