A groundbreaking advancement in the fight against refractory CD30-positive lymphomas has emerged from researchers at the Sant Pau Research Institute (IR Sant Pau), in conjunction with Sant Pau Hospital and the Josep Carreras Leukaemia Research Institute. They have developed an innovative chimeric antigen receptor T-cell (CAR-T) therapy known as HSP-CAR30, specifically engineered to target the CD30 protein, a marker expressed on Hodgkin lymphoma and some T-cell lymphomas. This therapeutic breakthrough, recently detailed in a Phase I clinical trial published in the prominent journal Blood, highlights the therapy’s potent ability to stimulate durable immune responses through the expansion of memory T cells, offering renewed hope for patients who previously faced limited treatment avenues.
The management of Hodgkin lymphoma and other CD30-positive lymphomas has persistently challenged oncologists, especially in cases resistant or recurrent after conventional treatment regimens. While CAR-T therapies have revolutionized treatments for certain hematologic cancers such as B-cell malignancies, their application in CD30-positive lymphomas has been restrained by issues involving the transient persistence of engineered T cells and high relapse rates. Compounding this challenge is the scarcity of clinical trials focused on this particular subset of lymphomas, slowing progress toward effective, long-lasting therapies. The introduction of HSP-CAR30 signifies a strategic leap forward in overcoming these barriers.
This new iteration of CAR-T treatment employs sophisticated genetic engineering enhancements that optimize T-cell functionality and longevity. HSP-CAR30 strategically targets a stable epitope on the CD30 antigen, mitigating the tumor’s capacity to elude immune surveillance through shedding of the protein into circulation. Concurrently, the manufacturing protocol incorporates cytokine support with interleukins IL-7, IL-15, and notably IL-21—cytokines known to encourage the development and proliferation of less differentiated T-cell subsets. These memory-like T cells are associated with sustained immunological protection, ensuring that therapeutic effects extend beyond initial tumor clearance.
In the clinical evaluation, ten patients afflicted with relapsed or refractory classical Hodgkin lymphoma or CD30-positive T-cell lymphoma underwent HSP-CAR30 therapy. Remarkably, the study attained a 100% overall response rate, a figure almost unparalleled in heavily pretreated patient populations. Half of the participants achieved complete remission, confirmed by imaging modalities and clinical assessments indicating an absence of measurable disease. These milestones were achieved without encountering dose-limiting toxicities—a significant consideration in cell-based therapies where adverse effects often pose serious obstacles to treatment continuation.
Durability of response remains a paramount objective in immunotherapy for cancer. The follow-up period, with a median of nearly three years, revealed that 60% of patients who had attained complete remission remained disease-free without relapse. This longitudinal persistence of remission correlates with sustained detection of CAR30-positive T cells in patient circulation, underscoring the importance of therapeutic cell persistence in enforcing durable cancer control. Neurosafety was particularly promising, with no neurotoxic events reported, while low-grade cytokine release syndrome was manageable in a subset of patients.
The cellular profile during peak therapeutic activity revealed an enhanced presence of central memory (TCM) and stem-like memory T cells (TSCM-like), less differentiated subsets known for their enhanced proliferative potential and longevity. This phenotype is believed to underpin the observed long-term benefits and reduced relapse propensity, setting this therapy apart from earlier CAR-T constructs. By retaining a reservoir of potent immune cells, HSP-CAR30 aims to establish an effective and persistent immunological defense against lymphoma recurrence.
Experts leading this research underscore the transformative potential of carefully selecting the CD30 epitope and fostering the ex vivo preservation of early-stage T-cell subsets. Dr. Ana Caballero, consultant hematologist and co-investigator, emphasizes that if larger trials confirm these findings, the approach could mark a paradigm shift in refractory CD30-positive lymphoma treatment. The technique promises renewed therapeutic hope for patients with previously limited options, highlighting the importance of translating advanced cellular immunology techniques into clinically viable interventions.
Following the successful Phase I trial, the study has progressed into Phase II, expanding the patient cohort to 32, with an additional 10 patients enrolled to enhance data robustness. Preliminary results from this extended evaluation are encouraging, with over 55% of participants achieving complete remission. These findings reinforce the therapy’s potential for broader clinical application and establish a foundation for ongoing optimization and eventual regulatory approval.
The therapeutic mechanism of CAR-T cells involves harvesting patient-derived T lymphocytes, genetically modifying them to recognize specific antigens on tumor cells—in this case, CD30—and reinfusing them to mount a targeted immune attack. By refining this approach through improved antigen targeting and cytokine-enhanced manufacturing, researchers have significantly enhanced both the efficacy and durability of the therapeutic cells, mitigating previous challenges related to T-cell exhaustion and tumor immune escape.
A vital element of this advancement is the strategic use of interleukin-21 partnered with IL-7 and IL-15 during T-cell expansion. IL-21’s role in promoting the generation of long-lived memory T cells differentiates the HSP-CAR30 manufacturing process from earlier CAR-T methodologies. This cytokine cocktail fosters a T-cell phenotype equipped to facilitate sustained immune surveillance, ensuring that patients maintain an active defense capable of preventing disease recurrence over extended periods.
From a production and quality control standpoint, the program has integrated stringent measures to ensure the viability and functional integrity of the modified T cells. Dr. Laura Escribà, Director of Quality Control for CAR30 Production, asserts that their goal is to provide patients not just with an initial therapeutic effect but with a long-lasting cellular arsenal able to respond swiftly if the lymphoma attempts to return. This commitment to high-quality manufacturing underpins the therapy’s safety and clinical effectiveness profiles.
The development and clinical testing of HSP-CAR30 have been supported by substantial funding from various institutions, including the Josep Carreras Leukaemia Foundation and the Josep Carreras Leukaemia Research Institute, which have invested significantly in infrastructure such as advanced cell production units. Their campaign, "The Unstoppable Cell Factory," raised essential funds to capitalize these facilities and enable the production of therapeutic doses for the initial patients. Additional support has come from public and private research funding bodies across Europe, enabling a robust translational research ecosystem critical for such pioneering work.
This trailblazing European study represents a significant milestone, successfully completing its initial Phase I clinical evaluation and presenting pivotal Phase II data at the 2024 American Society of Hematology (ASH) meeting. It highlights a model for future CAR-T development focused not only on direct tumor targeting but also on modulating the immune system’s memory capabilities to secure long-term remission and improve patient outcomes significantly.
With the convergence of genetic engineering, immunology, and advanced manufacturing, HSP-CAR30 stands as a beacon of innovation in the treatment landscape of CD30-positive lymphomas. If forthcoming larger-scale trials replicate these promising results, this therapy could fundamentally transform the prognosis for patients with refractory or relapsed disease, shifting the paradigm from palliative intent to potentially curative outcomes. The optimism stirred by these findings paves the way for a new chapter in cancer immunotherapy focused on tailored, durable, and highly effective cellular therapies.
Subject of Research: People
Article Title: HSP-CAR30 with a high proportion of less-differentiated T cells promotes durable responses in refractory CD30+ lymphoma
News Publication Date: 17-Apr-2025
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Caballero AC, Ujaldón-Miró C, Pujol-Fernández P, Montserrat-Torres R, Guardiola-Perello M, Escudero-López E, Garcia-Cadenas I, Esquirol A, Martino R, Jara-Bustamante P, Ezquerra P, Soria JM, Iranzo E, Moreno-Martinez M-E, Riba M, Sierra J, Alvarez-Fernández C, Escribà-Garcia L, Briones J. HSP-CAR30 with a high proportion of less-differentiated T cells promotes durable responses in refractory CD30+ lymphoma. Blood 2025;145:1788–801.
Image Credits: Josep Carreras Leukaemia Research Institute
