Novel CAR-T therapy achieves positive results in a high proportion of patients with a refractory type of lymphoma

Researchers from the Sant Pau Research Institute (IR Sant Pau), in collaboration with Sant Pau Hospital and the Josep Carreras Leukemia Research Institute, have developed an innovative CAR-T cell therapy targeting the CD30 protein (HSP-CAR30), which has shown high efficacy in patients with refractory CD30+ lymphoma.

A Phase I clinical trial, whose results have been published in the journal Blood, reveals that this new CAR-T30 therapy promotes the expansion of memory T cells, leading to long-lasting responses and improved clinical outcomes in treated patients.

Hodgkin lymphoma and other CD30⁺ lymphomas have posed a significant challenge to the medical community, particularly in refractory or relapsed cases where conventional treatments have so far shown limited efficacy.

Recently, CAR-T cell therapies have emerged as a promising alternative for treating hematological malignancies, achieving very positive results in B-cell leukemias and lymphomas. However, their application to CD30⁺ lymphomas has been limited due to the lack of persistence of modified cells and the high relapse rate among patients. Additionally, the exceptionally low number of clinical trials in this context has hindered the development of new solutions.

Thanks to advances in genetic engineering and biotechnology, the team at IR Sant Pau has overcome these challenges by developing HSP-CAR30, an optimized version of CAR-T therapy incorporating new strategies to improve the functionality and durability of therapeutic cells. This breakthrough represents a milestone in the fight against these types of cancer and opens new possibilities for patients who previously had very few treatment options.

The Phase I trial involved 10 patients with relapsed or refractory classical Hodgkin lymphoma or CD30⁺ T-cell lymphoma, yielding highly positive results.

Dr. Javier Briones, Head of the Hematological Oncology and Transplant Research Group at IR Sant Pau and Head of the Hematology Department at Sant Pau Hospital, led the study and states that its “most remarkable aspect is the 100% overall response rate, which is extremely rare in patients who have undergone multiple lines of treatment. Additionally, 50% of patients achieved complete remission, meaning the disease was undetectable in imaging studies and clinical analyses.”

Regarding the durability of the response, 60% of patients who achieved a complete response remained in remission with no signs of relapse after a median follow-up of 34 months. “This is crucial,” explains Dr. Briones, “because it indicates that the persistence of CAR-T cells in the body has a real and lasting impact on the disease, which is precisely what we aim for with this type of therapy.”

From a safety perspective, the treatment exhibited a favorable profile, with no dose-limiting toxicities detected. Six patients experienced Grade 1 cytokine release syndrome (CRS), and none developed neurotoxicity. The observed adverse effects were mild and manageable, reinforcing the feasibility of this therapy for clinical application.

One of the most significant findings of the study was the high in vivo persistence of CAR30⁺ cells, which remained detectable in 60% of evaluable patients one year after infusion. Furthermore, during the peak expansion of T cells, there was a predominance of central memory T cells (TCM) and stem-like memory T cells (TSCM-LIKE), which are associated with treatment efficacy and durability.

A promising future for patients with refractory lymphoma

“These results suggest that selecting the CD30 epitope and preserving less differentiated T cells ex vivo may enhance CAR-T therapy efficacy in patients with refractory Hodgkin lymphoma,” states Dr. Ana Caballero, Consultant Hematologist and co-investigator of the trial.

She highlights the significance of this discovery: “If we can demonstrate in larger studies that this strategy works long-term, we could be looking at a paradigm shift in the treatment of refractory CD30⁺ lymphomas. This would bring hope to many patients with very limited therapeutic options.”

The study is registered on ClinicalTrials.gov (NCT04653649) and is currently in an extended analysis phase to evaluate the efficacy of HSP-CAR30 in a larger cohort. If these results are confirmed in subsequent studies, this innovative therapy could represent a major advancement in combating this disease.

HSP-CAR30: A pioneering study in Europe

HSP-CAR30 is the first European CAR-T30 study to successfully complete its initial phase. The results of the Phase I trial, now published in Blood, and preliminary findings from the Phase II trial were presented at the 2024 annual meeting of the American Society of Hematology (ASH), one of the most significant scientific gatherings held at the end of last year.

To date, 32 patients have been treated with HSP-CAR30 in the Phase II trial, with an additional 10 patients included to strengthen the robustness of the findings. According to Dr. Caballero, this expansion will provide a more solid foundation for the future development of this therapy.

“The fact that over 55% of patients achieved complete remission in Phase II encourages us to move forward. These results are highly promising for a population with limited treatment options,” she stated.

A new approach to CAR-T therapy for CD30⁺ lymphoma

CAR-T cells act as a specialized immune force. These cells are extracted from the patient and modified in the laboratory to recognize and attack specific cancer cells. In this case, HSP-CAR30 is designed to target the CD30 protein, which is present on the tumor cells of Hodgkin lymphoma and other CD30⁺ lymphomas but rarely expressed on healthy cells.

Previous CAR-T therapies faced challenges where, despite their initial effectiveness, many of these cells became exhausted too quickly or lost their ability to fight cancer long-term. To overcome this, researchers optimized HSP-CAR30 to target a more stable region of the CD30 protein, preventing the tumor from evading attack by shedding CD30 fragments into the bloodstream.

Additionally, the manufacturing process has been refined to enhance the quality and persistence of modified T cells. An innovative strategy combining interleukin-21 (IL-21) with IL-7 and IL-15 has been implemented to promote the expansion of long-lived memory T cells. This ensures that the therapy is not only effective in the short term but also offers a greater likelihood of lasting protection against the disease.

Dr. Laura Escribà, senior researcher and Director of Quality Control for CART30 Production, explains, “The goal of this optimization is to ensure that CAR-T cells are not only effective at the outset but also remain active in the body for a much longer period. We want the patient’s immune system to retain a group of defense cells ready to act should the cancer attempt to return.”