Projects & Research

We are actively investigating the suppressive adenosine signaling pathway. Elevated extracellular adenosine in the tumor microenvironment suppresses immune responses and promotes tumor growth. We have shown that radiation increases adenosine levels and modulates key components of the adenosine pathway, including A2AR, A2BR, CD39, and CD73. In preclinical models, the combination of adenosine signaling modulators and radiotherapy significantly improves tumor control. Both preclinical and clinical studies are ongoing to explore this combination as a promising therapeutic strategy. Notably, we are studying this pathway across multiple malignancies, including its role in non-small cell lung cancer (NSCLC). An early phase clinical trial is underway testing the combination of an A2AR inhibitor, anti-PD-1 and tumor irradiation for patients with advanced NSCLC (NCT06116786).

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In partnership with the Division of Nuclear Medicine, the Spina Lab has an established platform to investigate the effects of radiopharmaceuticals in prostate cancer at the single cell level. We study how radiopharmaceuticals (e.g., ¹⁷⁷Lu-, ²²⁵Ac-based therapies) influence tumors, their microenvironment, and systemic immunity in patient biospecimens and advanced preclinical models (syngeneic, orthotopic, GEMMs). Our approach combines single-cell and spatial RNA sequencing with flow cytometry for immune profiling to dissect tumor–immune interactions and in situ investigations of DNA repair to uncover therapeutic vulnerabilities. This work addresses a key gap in understanding of precise mechanisms driving the therapeutic efficacy and resistance of radiopharmaceuticals in prostate cancer. Ultimately, we aim to inform combination treatment strategies and support the development of more effective, less toxic therapies.

SBRT-AMICO is a Phase 2, investigator-initiated clinical trial evaluating the safety and effectiveness of combining radiotherapy with three investigational immunotherapy agents—zimberelimab (anti–PD-1), etrumadenant (A2AR/A2BR inhibitor), and quemliclustat (CD73 inhibitor)—in men with hormone-sensitive oligometastatic prostate cancer. These therapies target the suppressive adenosine signaling pathway, active in tumors to evade immune destruction. Patients begin treatment with the adenosine pathway inhibitors, etrumadenant and quemliclustat, followed by oligometastsis-directed stereotactic body radiotherapy (SBRT), and then begin immune checkpoint inhibitor, zimberelimab. The trial aims to promote durable anti-tumor immune function and delay disease progression -- without hormonal therapy. We are conducting mechanistic investigations of paired pre- and on-treatment tumor biopsies and serial blood collected along the course of treatment.

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 Led by NRG Oncology, NRG GU0015 (ARCHER)  is a phase III, two-arm randomized non-inferiority clinical trial testing hypofractionated (20 fractions) versus ultra-hypofractionated (5 fractions) bladder chemoradiation for muscle-invasive bladder cancer (MIBC).  The SBRT arm will leverage technical advances in radiation planning and treatment delivery with adaptive plan-of-the-day or online adaptive technologies.  The primary endpoint is bladder-intact event-free survival (BI-EFS) at three years. Together with Co-Translational Science Chair Dr. David Miyamoto at MGH, we are leading exciting translational investigations including testing circulating tumor DNA (ctDNA) as an integrated biomarker to determine whether it is predictive of disease recurrence as a secondary outcome variable. A rich set of biospecimens (tumor, peripheral blood, urine) will be collected from trial participants for mechanistic investigations and biomarker discovery. 

The TRX project investigates strategies to enhance the efficacy of radiotherapy by targeting suppressive myeloid populations that emerge in response to treatment. Using integrated proteogenomic profiling alongside VIPER and OncoTarget analysis of CITE-Seq data, we identified  suppressive myeloid subpopulations that are enriched by tumor irradiation. Leveraging PLATE-Seq methodologies, we are conducting a high throughput screen of these suppressive tumor-infiltrating myeloid cells to identify novel pathways and targets unique to these unwanted cells. The goal is to move lead hits forward to develop a therapy for combination with radiation to restore anti-tumor immune responses and improve therapeutic outcomes.

In collaboration with the CZ BioHub and Dr. Jeremy Worley and Dr. Aleks Obradovic, this project aims to address the limited infiltration and activity of CAR-T cells in solid tumors that limits its clinical success . Using CRISPR engineering and advanced computational modeling, we aim to identify and validate key regulators of T cell tropism to solid tumors. The project integrates Dr. Worley’s GECO platform for T cell modification, with VIPER-based analysis of scRNASeq data and our Translational Tissue Processing Platform to enable in vivo validation in both mouse and patient-derived tumor models. This combined approach allows for high-resolution analysis of tumor–immune interactions at the single-cell level. The findings are designed to advance the development of next-generation CAR-T therapies for solid tumors.