Photoimmunotherapy is a new class of molecular targeted cancer therapy which was invented by Dr. Kobayashi. It is based on photoabsorber IRDye700 conjugated to a monoclonal antibody (mAb) against a surface antigen selectively expressed on cancer cells. Conjugate-bound cancer cells are rapidly and selectively killed upon NIR light illumination with a 689 nm laser. This type of therapy also induces a strong immune response by immunogenic release of tumor antigens from the damaged cancer cells. Photoimmunotherapy with cetuximab-IR700 conjugate targeting EGFR was approved in Japan in 2020 and is currently undergoing a global phase 3 clinical trial in patients with recurrent H&N cancer. Results so far have indicated this therapy to be superior to existing therapies for this patient population. Much of its success is owed to the strong immune response that photoimmunotherapy induces.
Motivation for the study
The motivation was to study if photoimmunotherapy could enhance anti-tumor immunity when combined with immune checkpoint inhibition. CD44-targeted photoimmunotherapy was applied against poorly immunogenic, “cold” tumor and antitumor effect was studied alone and in combination with anti-PD-1 immune checkpoint inhibition. Sensitization of this “cold” tumor to immune checkpoint inhibition after photoimmunotherapy would mean that the tumor has been converted into highly immunogenic, “hot” tumor infiltrated with killer T cells mainly responsible for eradicating the tumor. Also the formation of immunological antitumor memory after photoimmunotherapy was investigated.
The treatment efficacy of CD44-targeted NIR-PIT combined with anti-PD-1 immune checkpoint inhibition was studied in mice with subcutaneously allografted tumors. CD44-IR700 and anti-PD-1 were administered via intravenous and intraperitoneal injections, respectively. The tumors were then topically illuminated with a 689 nm laser at irradiance of 150 mW/cm2 until a dose of 50 J/cm2 was reached. A multi-channel ML7710 laser was used for these experiments to support parallel illumination of multiple test subjects. Acquired immunological memory was also studied using test subjects that had complete remission after the combination therapy. 100 days after the first tumor injection, new tumor cells were subcutaneously injected into the same side where the first tumor located and the tumor growth rate and survival of mice was monitored.
The therapeutic effect of anti-PD-1 immune checkpoint inhibition was substantially enhanced when combined with photoimmunotherapy. Post-treatment tumor size in the combination group was significantly lower at day 40 compared to groups receiving monotherapy (Figure 1). The survival of subjects in the combination group was also significantly prolonged compared to other groups (Figure 2). Moreover, the combination therapy yielded superior complete remission rates as high as 67%.
Figure 1. Tumor growth curves for each study group.
Figure 2. Kaplan-Meier survival analysis for each study group.
No tumor was established in mice that were re-challenged after complete remission, while tumors grew in all the control mice that had not originally received combination therapy (Figure 3). Kaplan-Meier analysis shows significantly better response in re-challenged mice compared to controls (Figure 4). Results indicate that the combination therapy produces strong immunological memory against the tumor.
Figure 3. Tumor growth curves for re-challenge 100 days after the first tumor injection.
Figure 4. Kaplan-Meier survival analysis for tumor re-challenge.
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