Classical Hodgkin lymphoma and other CD30-expressing lymphomas have long been entrenched as therapeutic challenges, particularly when standard regimens fall short in relapsed or refractory presentations. While CAR-T therapies have revolutionized treatment paradigms for B-cell malignancies by reprogramming immune cells to eradicate cancer, their deployment in CD30+ lymphoma patients has encountered obstacles, notably the limited persistence of infused CAR-T cells and rapid disease recurrence. Until now, the field has been constrained by a paucity of rigorous clinical investigations dedicated specifically to these lymphomas, stalling progress in their treatment.

The scientific team at IR Sant Pau employed advanced genetic engineering techniques to overcome these hurdles, culminating in the creation of HSP-CAR30—an optimized CAR-T construct designed to enhance both the longevity and antitumor activity of therapeutic lymphocytes. This refinement includes targeting a more stable epitope on the CD30 protein to prevent tumor immune evasion, a strategy informed by detailed molecular analyses revealing the structural vulnerabilities exploited during earlier therapy failures. This breakthrough holds transformative potential for patient populations previously deprived of effective options.

The Phase I trial enrolled a cohort of ten patients contending with relapsed or refractory classical Hodgkin lymphoma or CD30-positive T-cell lymphoma. Astonishingly, the overall response rate reached 100%, a stark contrast to historical outcomes in heavily pretreated cohorts. Notably, half of the participants achieved complete remission, verified through comprehensive imaging and exhaustive clinical evaluations. According to Dr. Javier Briones, lead investigator and director of Hematologic Oncology at IR Sant Pau, this unprecedented efficacy underscores the potent immune-mediated tumor suppression achievable with HSP-CAR30.

Beyond immediate efficacy, the trial highlighted the remarkable durability of responses, with 60% of patients maintaining remission at a median 34-month follow-up. This sustained disease control aligns with the therapy’s ability to establish long-lived memory T cells in vivo, specifically central memory (TCM) and stem cell-like memory (TSCM-like) subsets, which are known to underpin persistent immunosurveillance. Persistent CAR30+ cells were detectable in a majority of evaluable subjects even one year after infusion, marking a significant advancement over prior CAR-T constructs that succumbed prematurely to cellular exhaustion.

Safety evaluations revealed an encouraging toxicity profile. Treated patients predominantly experienced mild, grade 1 cytokine release syndrome (CRS), and crucially, no instances of neurotoxicity were observed. The absence of dose-limiting toxicities signals that HSP-CAR30 can be safely administered, expanding its therapeutic scope. This safety finding is pivotal for clinical translation, particularly given the fragile condition of patients battling relapsed lymphoma.

Central to the therapy’s efficacy is an innovative manufacturing process that integrates interleukins IL-7, IL-15, and IL-21 during ex vivo T-cell expansion. This cytokine cocktail preferentially promotes the generation of less differentiated memory T cells, conferring enhanced proliferative capacity and longevity upon reinfusion. By fostering a reservoir of potent, self-renewing T lymphocytes, HSP-CAR30 ensures sustained antitumor activity and mitigates premature immunologic attrition that has plagued previous CAR-T approaches.

This strategy coincides with deliberate targeting of a stable, non-shedding CD30 epitope, circumventing a key immune evasion mechanism employed by tumors. Earlier CAR-T therapies inadvertently targeted extracellular domains prone to fragment release, blunting immune recognition and facilitating relapse. The precise epitope selection in HSP-CAR30, backed by structural biology insights, represents an intelligent design shift that effectively barricades the therapeutic cells against tumor escape.

As the investigation progresses, Phase II data have already begun to illuminate the therapeutic horizon. Thirty-two patients have been treated with HSP-CAR30, with an expanded cohort adding ten more subjects to solidify findings. Preliminary analyses indicate that over 55% of these patients achieve complete remission, corroborating Phase I results and reinforcing confidence in this approach. The trial’s expansion aims to validate these promising outcomes within a larger, more diverse patient population.

Experts believe this therapy heralds a paradigm shift in treating refractory CD30+ lymphomas. Dr. Ana Caballero, co-investigator and hematology specialist, asserts that if these findings hold in subsequent larger-scale studies, HSP-CAR30 might establish a new standard of care for patients who have exhausted conventional treatments. The dual capability of potent immediate cytotoxicity combined with prolonged immunological memory offers a durable therapeutic platform.

On the technological front, quality control innovations have been critical. Dr. Laura Escribà, overseeing production quality, highlights the stringent manufacturing protocols that ensure consistency and functionality of the CAR-T cells. The incorporation of advanced cell culture techniques, alongside molecular engineering refinements, enables high-yield production of immunocompetent, long-lived CAR-T cells. These processes underscore the translational viability of HSP-CAR30 as a scalable off-the-shelf treatment for hematological malignancies.

The endeavor’s success owes much to multisectoral support. The Josep Carreras Foundation and Leukaemia Research Institute fortified the project with substantial funding and infrastructure, including the establishment of state-of-the-art cell production units at Sant Pau. Additional backing from institutions such as La Marató de TV3, “La Caixa” Foundation, Carlos III Health Institute, and European Union frameworks was instrumental. These collaborations exemplify how targeted investment in cutting-edge immunotherapy research can accelerate clinical breakthroughs.

In sum, HSP-CAR30 exemplifies the confluence of molecular engineering, immunology, and clinical acumen to surmount longstanding challenges in lymphoma therapy. By generating a reservoir of robust, memory-enriched CAR-T cells targeting a strategically chosen antigenic epitope, this therapy offers new hope for patients suffering from refractory CD30+ lymphomas. Future studies will determine if these groundbreaking Phase I and II results translate into long-term remission and survival benefits on a population scale.

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: 29-Apr-2025

Web References:
http://dx.doi.org/10.1182/blood.2024026758

References:
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;145:1788–1801.

Keywords: Cancer treatments, T cell lymphoma, Clinical research, Memory T cells, Clinical trials, Gene therapy, Blood diseases

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

Web References:

• https://doi.org/10.1182/blood.2024026758
• http://dx.doi.org/10.1182/blood.2024026758

References:
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