906 Early effector T-cell densities predict response in patients with advanced Merkel cell carcinoma treated with anti-PD-1

TPS219 Background: Talimogene laherparepvec, a modified herpes virus agent, induces a response in 65% of injected melanoma tumors. The combination of talimogene laherparepvec with ipilimumab or pembrolizumab appears promising in clinical trials of advanced melanoma. Talimogene laherparepvec-based therapy may be effective in other cancers of the skin and lymph nodes that are anatomically accessible for intratumoral injection. Methods: This phase II study will evaluate intratumoral talimogene laherparepvec monotherapy in 4 parallel disease cohorts: 1) Refractory T cell and NK cell lymphomas including cutaneous T cell lymphoma, 2) Merkel cell carcinoma 3) Cutaneous squamous cell carcinoma and 4) Other advanced/refractory non-melanoma skin cancers. Lymphoma patients must be refractory to or intolerant of all standard life-prolonging therapies. Skin cancer patients must be advanced/unresectable or refractory to one or more treatments including surgery, radiation therapy, or medical therapy. Prior PD-1-directed therapy is allowed. If an objective response is not achieved by Week 12, the PD-1 blocking antibody nivolumab will be added. The primary endpoint is the response rate with talimogene laherparepvec and secondary endpoints include response rate with the combination and overall survival. Using a two-stage design, if 1 or more response is observed in the first 9 patients in each parallel cohort, 8 additional patients will be accrued for a total sample size of 36 to 68 patients across the 4 disease cohorts. Tumor biopsies of injected lesions are mandatory at baseline and Week 6, and optional at Week 16 and the time of progression. Optional biopsies of non-injected lesions (when applicable) at Week 6 and 16 will be analyzed to identify biomarkers of systemic immunity. Tumor tissue and/or blood will be assayed for PD-L1 expression, RNA profiling, immune cell profiling, HVEM, NECTIN 1/2, IDO, tryptophan and L-kynurenine, mutational load, TIL TCR clonality, and prior exposure to herpes simplex type 1 virus and Merkel cell polyomavirus. Clinical trial information: NCT02978625.

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Viral and tumor antigen-specific CD8 T-cell responses in Merkel cell carcinoma

Cellular Immunology ◽

10.1016/j.cellimm.2019.103961 ◽

2019 ◽

Vol 344 ◽

pp. 103961 ◽

Cited By ~ 4

Author(s):

Mahtab Samimi ◽

Houssem Benlalam ◽

Pascal Aumond ◽

Pauline Gaboriaud ◽

Delphine Fradin ◽

...

Keyword(s):

T Cell ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Tumor Antigen ◽

T Cell Responses ◽

Cd8 T Cell ◽

Merkel Cell ◽

Cell Responses

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Selective reactivation of STING signaling to target Merkel cell carcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1919690117 ◽

2020 ◽

Vol 117 (24) ◽

pp. 13730-13739 ◽

Cited By ~ 3

Author(s):

Wei Liu ◽

Gloria B. Kim ◽

Nathan A. Krump ◽

Yuqi Zhou ◽

James L. Riley ◽

...

Keyword(s):

T Cell ◽

Cell Carcinoma ◽

Tumor Cells ◽

Merkel Cell Carcinoma ◽

Targeted Delivery ◽

Tumor Antigens ◽

Innate Immune ◽

Merkel Cell ◽

Adaptive Responses ◽

Chemokine Production

Merkel cell carcinoma (MCC) is a lethal skin cancer that metastasizes rapidly. Few effective treatments are available for patients with metastatic MCC. Poor intratumoral T cell infiltration and activation are major barriers that prevent MCC eradication by the immune system. However, the mechanisms that drive the immunologically restrictive tumor microenvironment remain poorly understood. In this study, we discovered that the innate immune regulator stimulator of IFN genes (STING) is completely silenced in MCCs. To reactivate STING in MCC, we developed an application of a human STING mutant, STINGS162A/G230I/Q266I, which we found to be readily stimulated by a mouse STING agonist, DMXAA. This STING molecule was efficiently delivered to MCC cells via an AAV vector. Introducing STINGS162A/G230I/Q266Iexpression and stimulating its activity by DMXAA in MCC cells reactivates their antitumor inflammatory cytokine/chemokine production. In response to MCC cells with restored STING, cocultured T cells expressing MCPyV-specific T cell receptors (TCRs) show increased cytokine production, migration toward tumor cells, and tumor cell killing. Our study therefore suggests that STING deficiency contributes to the immune suppressive nature of MCCs. More importantly, DMXAA stimulation of STINGS162A/G230I/Q266Icauses robust cell death in MCCs as well as several other STING-silenced cancers. Because tumor antigens and DNA released by dying cancer cells have the potential to amplify innate immune response and activate antitumor adaptive responses, our finding indicates that targeted delivery and activation of STINGS162A/G230I/Q266Iin tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-deficient cancers.

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