Cancer photo-immunotherapy: from bench to bedside

Abstract

Targeted therapy and immunotherapy in combination is considered the ideal strategy for treating metastatic cancer, as it can eliminate the primary tumors and induce host immunity to control distant metastases. Phototherapy, a promising targeted therapy, eradicates primary tumors using an appropriate dosage of focal light irradiation, while initiating antitumor immune responses through induced immunogenic tumor cell death. Recently, phototherapy has been employed to improve the efficacy of immunotherapies such as chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors. Phototherapy and immunoadjuvant therapy have been used in combination clinically, wherein the induced immunogenic cell death and enhanced antigen presentation synergy, inducing a systemic antitumor immune response to control residual tumor cells at the treatment site and distant metastases. This review summarizes studies on photo-immunotherapy, the combination of phototherapy and immunotherapy, especially focusing on the development and progress of this unique combination from a benchtop project to a promising clinical therapy for metastatic cancer.

Keywords: Cancer; combination therapy; immunotherapy; photo-immunotherapy; phototherapy.

Figure 1

An overview of cancer treatment using the combination of phototherapy and immunotherapy. Agents absorbed energy from light to kill tumor cells, by photochemical reaction in the case of PDT (Photodynamic therapy) and PIT (Photoimmunotherapy), or photophysical reaction in the case of PTT (Photothermal therapy). Induced tumor cell death with the release of antigens, DAMPs, and proinflammatory cytokines, can provide in situ autologous cancer vaccines. Immunoadjuvants or cytokines can enhance the antigen capture and presentation by APCs, which will amplify the subsequent systemic immune response, resisting the residual tumor cells in the primary sites while allowing the host to establish a long-term defense against homologous cancer. Checkpoint inhibitors (antibodies against PD‐L1, antibodies against CTLA-4, or small molecule IDO inhibitors) can further improve the treatment efficacy by blocking the immunosuppressive receptors on the cell surface, restoring the cytotoxic function of tumor-specific T-cells.

Figure 2

Tumor rechallenge of rats cured by LIT. Left table is the resistance to tumor challenge after laser immunotherapy treatment. The table is adapted with permission from , copyright 2001 American Association for Cancer Research. Right figure is the schematic of anti-tumor immunity induced by laser immunotherapy in tumor rechallenge. The figure is adapted with permission from , copyright 2015 Elsevier Ireland Ltd.

Figure 3

LIT (PTT+GC) induced tumor-specific immune memory. In vivo time-lapse images showing migration of endogenous GFP⁺ TILs in the CFP-B16 tumor area of CXCR6-GFP mice treated by LIT and rechallenged with CFP-B16. Scale bar: 70 μm. The figure is adapted with permission from , copyright 2020 Ivyspring International Publisher.

Figure 4

Photographs and CT images of a patient with stage IV melanoma during treatment. Upper: Photographs of the LIT treatment areas around the left ear. A. The primary tumor site with only surgical scars visible. B. The areas of biopsy-proven cutaneous recurrences around 2 surgical scars from the biopsy sites. Scalp hair has been trimmed away from the scalp recurrence site to make superficial laser therapy more effective. Reddish areas around the surgical scars represent melanoma deposits in the superficial dermis. C. Areas circled in red represent the 4 treatment sites selected for LIT. All other areas of regional involvement completely resolved during the 4-week treatment phase, which is typically seen with superficial LIT. D. The treatment area after LIT. Three months later, the LIT treatment completely cleared all cutaneous melanoma around the left ear. Bottom: CT images of the patient taken 3 months apart showing the same level in the thorax. A. The image was taken before ipilimumab treatment (2 months following LIT) and demonstrates the size and location of the pulmonary metastases. B-C. The images show shrinkage of the pulmonary metastases 3 months (B) and 6 months (C) after completion of the combination of LIT and ipilimumab. D. The image shows that pulmonary metastases were completely resolved 9 months after completion of the combination of LIT and ipilimumab. The figure is adapted with permission from , copyright 2017 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim.