Combining photoimmunotherapy with immune checkpoint inhibition

Customer case

The Laboratory of Molecular Theranostics at National Cancer Institute (NCI) is a major research section of the Molecular Imaging Program at National Cancer Institute (NCI) and is led by Dr. Hisataka Kobayashi who is the father of photoimmunotherapy. The ground-breaking research includes the development of imaging and theranostic probes with a particular emphasis on optical probes, which can aid in cancer detection during cancer resection or endoscopy.

Dr. Hisataka Kobayashi M.D., PhD

Dr. Peter L. Choyke M.D., PhD


Modulight products: ML7710 (multiple channels on 689 nm, 2 W)

Laser use: ML7710 for high-throughput in vivo illumination to study the photoimmunotherapy of cancer targeted against various molecular targets including EGFR, HER2, CTLA-4, and CD25.

Link to the study:


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. 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 the 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.




Graphs from the original publication. Reproduced under CC BY 4.0 International License.



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.


Graphs from the original publication. Reproduced under CC BY 4.0 International License.



Cancer-targeting photoimmunotherapy was shown to convert a minimally immunogenic tumor into immunologically “hot” tumor, leading to improved efficacy of the anti-PD-1 immune checkpoint inhibition. Combination of photoimmunotherapy and immune checkpoint inhibition led to reduced tumor growth, prolonged survival, and high complete remission rates.  Long-term immunological memory was also produced to prevent future recurrencies. Altogether, photoimmunotherapy could be in future beneficial immunological neoadjuvant for immune checkpoint inhibitors.


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Related Publications

Increased Immunogenicity of a Minimally Immunogenic Tumor after Cancer-Targeting Near Infrared Photoimmunotherapy
Hiroaki Wakiyama, Aki Furusawa, Ryuhei Okada, Fuyuki Inagaki, Takuya Kato, Yashuro Maruoka, Peter L. Choyke, Hisataka Kobayashi
Cancers, 2020, 12 (12)




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