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 Phase I trial results, recently published in the esteemed journal Nature Medicine, revealed an extraordinary overall response rate of 92.9% with a complete response rate hitting 66.7%. These figures were derived from a cohort of 42 heavily pretreated patients, meaning they had undergone numerous prior therapies and were still persistent in their illness. Such promising statistics signal not only a potential new direction for treating refractory lymphomas but also the flexibility of this strategy to be adapted for broader types of cancer as research progresses.

Principal investigator Dr. Yago Nieto, who serves as a professor in the Stem Cell Transplantation & Cellular Therapy department at MD Anderson, articulated the significance of these findings. He underscores the rapid and potent responses observed in patients treated with the AFM13-NK cells, affirming the ongoing evaluations of the therapy’s effectiveness in tackling challenging malignancies. His enthusiasm points to a larger ambition that this therapeutic innovation may serve either as a curative measure for some patients or act as a crucial bridge to potentially life-saving stem cell transplants.

The methodology behind this trial hinges on the unique characteristics of Affimed’s AFM13 bispecific antibody. This engineered molecule is specifically designed to bind with CD16A on NK cells and detects CD30 on malignant lymphoma cells. With this pre-complexing approach, AFM13-NK cells are empowered to better target and obliterate CD30-positive lymphoma cells. The process involves initially activating the NK cells using cytokines, expanding them in conjunction with artificial antigen-presenting cells, and then combining them with the AFM13 antibody before infusing them into the patient’s bloodstream.

The laboratory contributions of Dr. Katy Rezvani, who holds the Sally Cooper Murray Endowed Chair in Cancer Research, are fundamental to the development of this cell therapy. As the vice president of the Institute for Cell Therapy Discovery & Innovation at MD Anderson, Dr. Rezvani has been pivotal in advancing cell therapies, highlighting a concerted effort towards developing impactful innovations for multiple medical conditions.

The trial specifically included 37 adult patients with known CD30-positive Hodgkin lymphoma and an additional five with T-cell lymphoma. Notably, all participants had been heavily pretreated and had demonstrated non-responsiveness to established therapies, such as brentuximab vedotin and the anti-PD1 immune checkpoint inhibitors. The trial participants had a median age of 43 years, with an alarming median of seven prior lines of treatment, showcasing the dire circumstances faced by these patients when entering the study.

The trial involved administering a series of two to four cycles of chemotherapy, subsequently followed by infusions of the AFM13-NK cells at three different dose levels across three weekly sessions. Each treatment cycle concluded with a rigorous evaluation of each participant’s treatment response on day 28, along with structured follow-ups every three months to monitor their ongoing health status.

The results were not just numeric; they painted a picture of hope. The overall response rate (ORR) and complete response (CR) rates among study participants stood at an impressive 92.9% and 66.7%, respectively. Among those diagnosed with Hodgkin lymphoma, the statistics climbed even higher, with ORR and CR reaching 97.3% and 73%. Such results, particularly when benchmarked against this heavily pretreated patient pool, underscore the noteworthy effectiveness of the AFM13-NK cell therapy in these challenging cases.

Over a median follow-up period of 20 months, the two-year event-free survival (EFS) and overall survival (OS) rates for participants were reported as 26.2% and 76.2%, respectively. Given the refractory nature of the tumors exhibited by participants, these survival rates are particularly encouraging, reinforcing the therapy’s potential impact on long-term patient outcomes.

Despite the complexity of the treatment, patients tolerated the AFM13-NK cell therapy well, with no documented instances of cytokine release syndrome, neurotoxicity associated with immune cells, or graft-versus-host disease, which are common complications in such treatments. The only adverse event noted was a Grade 2 infusion-related reaction, suggesting the treatment’s safety profile is remarkably favorable compared to other emerging therapies.

Cord blood units selected for each treatment cycle were sourced from the MD Anderson Cancer Center Cord Blood Bank, adhering to strict criteria established for optimal donor cell characteristics. This attention to donor cell quality ensured that NK cells reached peak levels in patient blood one day following infusion, with a notable persistence of healthy donor cells up to three weeks, effectively enabling them to migrate towards tumor sites.

In conclusion, the trial demonstrated a promising safety profile and an encouraging level of efficacy for AFM13-NK cells specifically in patients dealing with refractory CD30-positive Hodgkin lymphoma. Dr. Yago Nieto’s statement reflects a growing optimism about the potential applications of this cell therapy methodology, suggesting it could not only revolutionize treatment protocols for Hodgkin lymphoma but also lay the groundwork for future research involving NK cells used in conjunction with bispecific engagers for various malignancies.

The research was supported by Affimed, with additional funding from MD Anderson and contributions from the National Institutes of Health. With the trial continuing to gather insights and data, medical professionals remain hopeful about translating these findings into widespread clinical practice, ultimately enriching the therapeutic options available for patients battling difficult-to-treat cancers.

Subject of Research: Novel cell therapy using NK cells for refractory CD30-positive lymphomas
Article Title: Innovative Cell Therapy Offers Hope for Refractory CD30-Positive Lymphoma Patients
News Publication Date: [Not Provided]
Web References: [Not Provided]
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Keywords: Natural killer cells, cancer patients, Hodgkin lymphoma, CD30, cell therapy, bispecific antibodies.