[ICKSH 2025] CAR-T therapy reshapes lymphoma treatment amid new strategies and resistance challenges

Chimeric Antigen Receptor T-cell (CAR-T) therapies are emerging as a powerful option for patients with lymphoma, especially those who have not responded to conventional treatments.

By reprogramming a patient’s immune cells to target and destroy cancer cells, CAR-T has demonstrated high response rates across multiple lymphoma subtypes in clinical trials. While safety concerns such as potential secondary malignancies have been raised, recent findings suggest the risk is comparable to existing therapies.

As research advances, CAR-T continues to reshape the standard of care in hematologic cancers.

Against this backdrop, Korea Biomedical Review met with Dr. Sattva S. Neelapu from the University of Texas MD Anderson Cancer Center during the International Congress of the Korean Society of Hematology (ICKSH) 2025, held at Grand Walkerhill Seoul from March 27 to 29, to hear about the current state and future prospects of CAR-T cell therapy for lymphomas.

The evolving treatment landscape

When discussing how CAR-T cell therapy and bispecific antibodies should be positioned in the treatment of relapsed/refractory B-cell lymphoma, Neelapu emphasized their complementary nature.

"Currently, CAR-T cell therapy targets the CD19 molecule, whereas bispecific antibodies target CD20, at least in the U.S.," he said.

CAR-T therapy has demonstrated remarkable efficacy, showing improved progression-free survival and overall survival rates.

Long-term data from pivotal trials like ZUMA-1 (Yescarta, axicabtagene ciloleucel), JULIET (Kymriah, tisagenlecleucel), and TRANSCEND (Breyanzi, lisocabtagene maraleucel) have confirmed what researchers hoped to see—survival curves reaching a plateau with approximately 30-40 percent of patients achieving durable remissions.

This success isn't limited to clinical trials, as real-world data from the U.S. Lymphoma CAR-T Consortium has shown similar outcomes, even though nearly half of those patients wouldn't have met the eligibility criteria for the original clinical trials.

"CAR-T therapy is approved in the second-line setting, whereas bispecifics are approved in the third-line setting," Neelapu said. "At this point, we still prefer CAR-T cell therapy as the preferred option in the third-line setting as well."

This preference is grounded in data. While bispecific antibodies have shown impressive response rates, Neelapu pointed out that it is not yet clear whether these are curative for large B-cell lymphoma and follicular lymphoma because at three to four years, hospitals have not yet seen a plateau in the progression-free survival curve.

Recent trials like ZUMA-7 (Yescarta, axicabtagene ciloleucel) and TRANSFORM (Breyanzi, lisocabtagene maraleucel) have demonstrated that CAR-T therapy significantly outperforms autologous stem cell transplantation in the second-line setting, establishing it as the standard of care for this indication in the U.S.

Looking ahead, Dr. Neelapu believes the treatment landscape will continue to evolve.

"In the future, we do see that bispecific antibodies are being evaluated in the first-line setting in combination with chemo-immunotherapy, and if the trials are positive, they're likely to become the standard of care in the first-line setting,” he said.

Overcoming resistance and future directions

One of the major challenges with CAR-T therapy is resistance. Dr. Neelapu identified three broad categories of resistance mechanisms.

"One group of patients, about a third of the patients, relapse because of antigen loss, there's another third of patients who relapse because of T-cell fitness issues that mediate resistance to CAR-mediated killing of the tumor cells, and the last is intrinsic tumor resistance, which occurs when tumor cells develop the ability to evade destruction by CAR-T cells, despite the presence of the targeted antigen and functional CAR-T cells,” he said.

Several strategies are being explored to enhance CAR-T efficacy and one promising approach involves targeting multiple antigens.

"To improve efficacy of CAR-T therapy, one way is to target multiple antigens, and this can be done by bispecific CAR-T therapies," Neelapu said. "Currently, CD19 and CD20 bispecific or CD19 and CD22 bispecific CARs, as well as those targeting CD20 and CD79A/B, are all being evaluated in the clinic."

T-cell fitness is another critical factor affecting CAR-T outcomes. Prior treatments, especially bendamustine, can significantly impact T-cell function.

"What's been shown in chronic lymphocytic leukemia is that if patients are treated with ibrutinib before they undergo apheresis, this appears to improve the T-cell fitness and yields a much better CAR-T cell product,” Neelapu said.

The tumor microenvironment also plays a crucial role in CAR-T efficacy.

Recent research presented at ASH 2024 categorized lymphoma microenvironments into lymph node (LN), fibroblast/macrophage (FMAC), and T exhausted (TEX) types. CAR-T therapy showed the greatest benefit in the LN subtype, followed by FMAC, while in the TEX subtype, outcomes were similar to conventional cytotoxic chemotherapy and autologous stem cell transplantation.

When asked about allogeneic (off-the-shelf) CAR-T therapy, Neelapu acknowledged both its potential and limitations.

"Allogeneic CAR-T therapies are fairly well tolerated with respect to cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome,” the U.S. professor said. “They're either similar to autologous CARs or safer than autologous CARs."

The main advantage of allogeneic CAR-T is the elimination of manufacturing time, allowing immediate treatment.

However, challenges include graft-versus-host disease (GVHD) and immune rejection.

Neelapu added that GVHD can be addressed through T-cell receptor removal or using alternative cell types like NK cells.

For immune rejection, researchers are exploring intensified lymphodepletion before CAR-T infusion and "hypoimmune" strategies to reduce the donor cells' visibility to the host immune system.

"Durability of the responses so far has been poor in allogeneic CAR-Ts, largely because we did not see persistence beyond four weeks in the majority of these patients," Neelapu noted.

Despite this limitation, some patients in the ALPHA 1 and 2 trials of cemacabtagene ansegedleucel showed durable remissions. A phase 3 trial (ALPHA 3) is now evaluating this treatment for large B-cell lymphoma patients with minimal residual disease after standard first-line therapy.

Regarding follicular lymphoma, CAR-T therapy has shown promising results, though the survival curves haven't yet reached a clear plateau.

Neelapu explained that the recurrence patterns differ significantly between large B-cell lymphoma and follicular lymphoma.

In the ZUMA-5 trial, which evaluated Yescarta (ingredient: axi-cel) in follicular lymphoma, median progression-free survival was 62.2 months after five years of follow-up. Most disease progression events occurred within the first two years, while non-disease-related events continued beyond that timeframe.

Analysis of lymphoma-specific disease-free survival suggests that approximately 60 percent of follicular lymphoma patients may achieve a cure with CD19 CAR-T cell therapy.

Looking to the future, Dr. Neelapu is particularly excited about emerging applications of CAR-T therapy. His team at MD Anderson is exploring innovative approaches.

"At our center, we are evaluating CAR-T therapy in combination with bispecific antibodies to minimize antigen loss and improve efficacy in these patients,” he said.

He also touched on the possibility of CAR-T therapy for T-cell lymphomas, which presents unique challenges.

Unlike B-cell aplasia, which can be managed with immunoglobulin replacement, pan-T-cell aplasia would pose life-threatening infection risks.

One promising approach targets CXCR5, which is expressed on mature B cells, skin-derived migratory dendritic cells, and follicular helper T cells.

Anti-CXCR5 CAR-T cells have shown efficacy against CXCR5-positive H9 cell lines and in mouse models, suggesting potential clinical applications.

As CAR-T therapy continues to evolve, Neelapu's work remains at the forefront of this revolutionary approach to cancer treatment.

"In the future, to make these therapies even more effective, we need strategies to better overcome immune rejection and improve expansion and persistence, and thereby durability of responses," he concluded.