Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer

Sep 24, 2026

Immunotherapies are increasingly used for advanced cancers, but resistance to immune checkpoint inhibition limits benefit, motivating combination strategies. This study evaluates whether pairing an oncolytic virus with radiation therapy can improve outcomes, and whether adding PD-1 checkpoint blockade yields enhanced triple-combination antitumor activity. In vitro and mouse model experiments show reduced tumor growth, increased PD-1/PD-L1 expression, and CD8+ T cell- and IL-1α-dependent mechanisms. A PD-1-refractory cutaneous squamous cell carcinoma patient experienced durable, unexpected tumor control and prolonged survival.

LanguageEnglish

CategoryResearch & Report

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Pages9

Reading Time23 min

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Abstract

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Background

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Open access Original research Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer Sachin R Jhawar,1 Shang-Jui Wang,1 Aditya Thandoni,2 Praveen K Bommareddy ,3 Jenna H Newman,3 Eileena F Giurini,4 Amanda L Marzo,4 Timothy M Kuzel,4 Vineet Gupta,4 Jochen Reiser,4 Preston Daniels,4 Devora Schiff,3 Darrion Mitchell,1 Nicole R LeBoeuf,5,6 Christopher Simmons,7 Sharad Goyal,8 Ahmed Lasfar,3,9 Jose A Guevara-Patino ,10 Bruce G Haffty,3 Howard L Kaufman ,11 Ann W Silk ,5,7 Andrew Zloza 4 To cite: Jhawar SR, Wang S-J, Thandoni A, et al. Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD- 1-refractory cancer. Journal for ImmunoTherapy of Cancer 2023;11:e006780 . doi:10 . 1136/ jitc-2023-006780 ► Additional supplemental material is published online only. To view, please visit the journal online ([http://dx.doi.org/10](http://dx.doi.org/10) . 1136/jitc-2023-006780) . Accepted 16 June 2023 © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. For numbered affiliations see end of article. Correspondence to Dr Ann W Silk; [ann_silk@dfci.harvard.edu](ann_silk@dfci.harvard.edu) Dr Andrew Zloza; [andrewzloza@gmail.com](andrewzloza@gmail.com) ABSTRACT Background Immunotherapies are becoming front-line treatments for many advanced cancers, and combinations of two or more therapies are beginning to be investigated. Based on their individual antitumor capabilities, we sought to determine whether combination oncolytic virus (OV) and radiation therapy (RT) may improve cancer outcomes. Methods To investigate the activity of this combination therapy, we used in vitro mouse and human cancer cell lines as well as a mouse model of skin cancer. After initial results, we further included immune checkpoint blockade, whose addition constituted a triple combination immunotherapy. Results Our findings demonstrate that OV and RT reduce tumor growth via conversion of immunologically ‘cold’tumors to ‘hot’, via a CD8+ T cell-dependent and IL-1α -dependent mechanism that is associated with increased PD-1/PD-L1 expression, and the triple combination of OV, RT, and PD-1 checkpoint inhibition impedes tumor growth and prolongs survival. Further, we describe the response of a PD-1-refractory patient with cutaneous squamous cell carcinoma who received the triple combination of OV, RT, and immune checkpoint inhibitor (ICI), and went on to experience unexpected, prolonged control and survival. He remains off-treatment and is without evidence of progression for >44 months since study entry. Conclusions Effective systemic antitumor immune response is rarely elicited by a single therapy. In a skin cancer mouse model, we demonstrate improved outcomes with combination OV, RT, and ICI treatment, which is associated with mechanisms involving augmented CD8+ T cell infiltration and IL-1α expression. We report tumor reduction and prolonged survival of a patient with skin cancer treated with combination OV, RT, and ICI. Overall, our data provide strong rationale for combining OV, RT, and ICI for treatment of patients with ICI-refractory skin and potentially other cancers. WHAT IS ALREADY KNOWN ON THIS TOPIC | ⇒ Talimogene laherparepvec (T-VEC) is the first oncolytic virus approved for the treatment of melanoma where it has a 31 .5% objective response rate. T-VEChas been evaluated in combination with immune checkpoint blockade and radiation therapy demonstrating improved therapeutic activity in patients with melanoma and in murine tumor models, although the mechanism(s) underlying this antitumor immunity is/are unclear.
WHAT THIS STUDY ADDS | | --- | | ⇒ Combination of a murine-adapted T-VEC and radiation therapy enhanced therapeutic responses were dependent on IL-1α and induced high expression of PD-L1 . Triple treatment with mT-V

FAQs

What question does the study address about anti-PD-1-refractory cancer?

It tests whether combining an oncolytic virus with radiation therapy improves outcomes, and whether adding immune checkpoint inhibition creates a more effective triple combination for anti-PD-1-refractory disease.

How was the therapy activity investigated?

The study used in vitro mouse and human cancer cell lines and a mouse model of skin cancer, and then incorporated immune checkpoint blockade to form a triple combination approach.

What mechanisms and outcomes were observed?

The combination reduced tumor growth by converting immunologically ‘cold’ tumors to ‘hot’ tumors through CD8+ T cell- and IL-1α-dependent mechanisms linked to increased PD-1/PD-L1 expression. The triple combination impeded tumor growth and prolonged survival, including a durable response in a PD-1-refractory patient.

Sep 24, 2026

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