Systemic Antitumor Immunity by PD-1/PD-L1 Inhibition Is Potentiated by Vascular-Targeted Photodynamic Therapy of Primary Tumors

Abstract

PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors, including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies and then examined treatment responses, including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed. Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases, and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8:regulatory T cell (Treg) and CD4FoxP3-:Treg ratios in primary renal tumors and increased T-cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone. .

Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood

“…It is well known that the TME and response of various syngeneic models to IV therapy encompasses a wide range of immunogenicity, tumor heterogeneity, and variability often relating to tumor age and size. Additionally, treatment results often differ depending on orthotopic or xenograft site of tumor cell inoculation [4,5]. In Renca tumors, it has been found that there is a general decrease in immune cell abundance as tumors increase in size beyond 100 mm 3 [4].…”

“…The inhibition of the human renal cell adenocarcinoma line 786-O [1] and the Renca murine renal cancer model by direct injection of NanoDoce versus the transient or minimal tumor reduction following IV docetaxel therapy has encouraged us to conduct a clinical trial in patients with renal cell carcinomas in which NanoDoce will be directly injected into localized tumors under image guidance. It is hypothesized that following IT NanoDoce treatments, patients with activated immune responses in the TME may develop efficacious acute and prolonged responses to immunotherapies (IO) [5]. The long residence time of NanoDoce particles may facilitate a continuous availability of tumor specific antigens allowing for prolonged immune response to initial antigens as well as reflective immune cell changes as antigens are modified.…”

Photodynamic Therapy and Immunity: An Update

“…Neither treatment alone was efficacious. Efficacy of the combination therapy was attributed to an increase in the ratio of CD8 + and CD4 + T cells to Tregs (109). Santos et al .…”

“…Targeted delivery of PS and checkpoint inhibitor delayed of tumor regrowth, prevented lung metastasis and caused systemic increase of CD8 + T cells (124). Hybrid nanoparticles that release PS and glucocorticoid‐induced TNF receptor family‐related protein/poly(lactic‐coglycolic acid) (GITR‐PLGA) take advantage of the immune activating role of PDT and GITR‐PLGA‐mediated inhibition of immunosuppression to enhance the number of antitumor CD8 + T cells in the tumor (109).…”

A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

“…In this manner, the PS is passively distributed mainly in the vascular compartment 3. The representative product, WST‐11 (TOOKAD soluble, padeliporfin) developed by STEBA Biotech, has entered into phase III in Europe and recently been approved for use in early‐stage prostate cancer in Mexico 4. In order to strengthen the vascular‐targeted efficacy, other attempts have involved conjugating vascular targeting ligands to the PS or PS nanocarrier to directly target the PS to tumor neovasculature 5.…”