In a groundbreaking step toward addressing the challenges faced by people living with HIV (PLWH) who develop Kaposi’s Sarcoma (KS), researchers have unveiled the STARKAP protocol—a preliminary assessment probing the safety and tolerability of dostarlimab in treating cART-refractory HIV-associated Kaposi’s Sarcoma. This novel approach combines immune checkpoint inhibition with the ongoing battle against this virally induced malignancy, setting a promising horizon in oncological and infectious disease management.

Kaposi’s Sarcoma, a vascular tumor derived from mesenchymal tissue, arises due to infection with human herpesvirus-8 (HHV-8). Despite significant advances brought about by the widespread use of combined antiretroviral therapy (cART), KS stubbornly remains the most prevalent neoplasia in the HIV-positive population globally. Although cART has dramatically lowered KS incidence over the years, upwards of 15-20% of cases fail to respond adequately, underpinning an urgent need for novel therapeutic strategies beyond the traditional antiviral paradigm.

The persistent nature of KS in a subset of patients is believed to be tightly linked with immune system dysfunction—specifically T-cell exhaustion, a state where immune cells lose their ability to effectively recognize and eliminate infected or malignant cells. Central to this dysfunction is the programmed cell death protein 1 (PD-1) pathway, an immune checkpoint that negatively regulates T-cell activity. The overexpression of PD-1 on T-cells in cART-refractory KS presents a compelling therapeutic target, as blocking this checkpoint could potentially reinvigorate immune responses against KS tumors.

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Capitalizing on this rationale, the STARKAP study introduces dostarlimab, a monoclonal antibody specifically engineered to block PD-1. Dostarlimab has shown promise in multiple cancer settings by effectively restoring T-cell functionality and enhancing anti-tumor immunity. The STARKAP protocol seeks to explore whether this immune checkpoint inhibitor can be safely combined with ongoing cART regimens in individuals with refractory KS, offering a lifeline where currently treatment options are limited.

Structured as an open-label, single-arm phase Ib trial, the study aims to enroll 20 patients diagnosed with cART-refractory KS. After an initial screening phase to confirm eligibility, participants receive dostarlimab administered intravenously at 500 mg every three weeks for the first five cycles, transitioning thereafter to 1000 mg every six weeks. The purpose of this dosing schedule is to optimize therapeutic exposure while closely monitoring safety and tolerability over up to a year of treatment.

The trial design incorporates a safety lead-in phase with the first six patients to diligently assess for any dose-limiting toxicities within 21 days post-treatment initiation. Absence of such toxicities would permit progression with the remaining trial subjects—an essential step ensuring patient safety in this vulnerable population. Patients will then be observed for adverse events for a further 90 days post the last dose, providing a comprehensive safety profile.

Alongside safety, secondary objectives encompass evaluating efficacy through tumor response rates using both the AIDS Clinical Trial Group (ACTG) criteria and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 when visceral disease is present. These standardized assessment techniques afford rigorous and quantifiable measures of treatment impact, permitting meaningful interpretation of therapeutic benefit.

An innovative translational component within the STARKAP study involves the longitudinal collection of tissue, blood, and stool samples. These specimens gathered at baseline, during treatment, and at treatment conclusion aim to unravel mechanistic insights into how dostarlimab modulates the immune milieu and viral dynamics in KS. Such analyses may illuminate biomarkers predictive of response, resistance pathways, and potential avenues for enhancing future therapies.

The intersection of immunotherapy and viral oncology embodied in this study signifies a paradigm shift. While immune checkpoint inhibitors like dostarlimab have revolutionized cancer treatment broadly, their application in virally driven neoplasms such as KS remains underexplored. STARKAP thus serves as a vanguard investigation, testing whether rejuvenating the immune system can decisively counteract KS that has eluded conventional cART control.

Clinical translation of findings from STARKAP could herald broader implications beyond KS. Chronic viral infections compounded by immunosuppression present a complex therapeutic landscape. Successful integration of PD-1 blockade in this context may encourage similar strategies for other virally linked malignancies or diseases characterized by immune exhaustion, expanding the boundaries of immuno-oncology.

Moreover, this trial addresses a critical unmet need in HIV care. KS disproportionately affects disadvantaged populations, and cART-refractory disease frequently portends poor outcomes. Introducing a safe and tolerable immune-based intervention could transform the therapeutic outlook, reducing morbidity and enhancing quality of life for these patients.

Equally important is the meticulous safety monitoring framework embedded within the protocol. The phased enrollment and extended post-treatment observation underscore the commitment to balancing innovation with patient welfare. Historical concerns about immune-related adverse events with checkpoint inhibitors necessitate such vigilance, especially in the immunocompromised HIV-positive cohort.

The STARKAP trial thus encapsulates a convergence of cutting-edge immunotherapy, infectious disease expertise, and oncological rigor. As the first clinical exploration of dostarlimab in this setting, the outcomes may pave the way for larger, controlled studies designed to validate efficacy and optimize patient management protocols.

In the broader scope of cancer research, STARKAP exemplifies the evolving recognition that tumors cannot be viewed in isolation but must be understood within the host’s immune and virological context. Such integrated approaches promise more personalized, effective treatments that address the multifaceted drivers of malignancy.

While awaiting the trial’s full results, the scientific and medical communities eagerly anticipate insights that may revolutionize care for patients grappling with this challenging and devastating disease. Should dostarlimab demonstrate favorable safety and preliminary efficacy, it could signal a major leap forward in harnessing the immune system’s power to fight virally associated cancers.

The STARKAP protocol underscores how collaboration across disciplines—from oncology, immunology, virology, to pharmacology—fuels innovations that transcend traditional boundaries. As research continues to unravel the complexities of immune evasion and viral oncogenesis, such pioneering clinical trials remain critical catalysts propelling the field toward more hopeful therapeutic landscapes.

In summary, the preliminary assessment of dostarlimab in cART-refractory HIV-associated Kaposi’s Sarcoma offers a bold and scientifically grounded attempt to overcome a stubborn clinical challenge. With rigor, precision, and patient-centered focus, STARKAP stands poised to unlock new chapters in the fight against this formidable malignancy.

Subject of Research: Safety and tolerability assessment of dostarlimab, a PD-1 blocking antibody, in combination antiretroviral therapy (cART)-refractory HIV-associated Kaposi’s Sarcoma.

Article Title: STARKAP Protocol: preliminary assessment of safety and tolerability of dostarlimab in combination antiretroviral therapy (cART)-refractory HIV associated Kaposi’s Sarcoma.

Article References:
Fulgenzi, C.A.M., Dalla Pria, A., Leone, A.G. et al. STARKAP Protocol: preliminary assessment of safety and tolerability of dostarlimab in combination antiretroviral therapy (cART)-refractory HIV associated Kaposi’s Sarcoma. BMC Cancer 25, 1104 (2025). https://doi.org/10.1186/s12885-025-14326-2

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14326-2

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