Strategies to Improve Manufacturing Time, Mitigate Toxicities of CAR T-Cell Therapy Remain a Focus in R/R LBCL

Hemant S. Murthy, MD

Although CAR T-cell therapy have emerged as an effective treatment option for select patients with relapsed/refractory large B-cell lymphoma (LBCL), improving strategies to mitigate and manage toxicities associated with this treatment and finding ways to increase the manufacturing times of these products remains of paramount importance, according to Hemant S. Murthy, MD.

“There's a multifaceted approach in improving outcomes of CAR T-cell therapy in [patients with] diffuse large B-cell lymphoma [DLBCL]. First, with our existing products, how do we get [these therapies] to more patients? We need to make it safer. We need to improve the manufacturing process so it can be administered to patients, [including those who] are frail or older, and it could be cost effective when you have patients with less toxicity and faster manufacturing [times with] less need for bridging therapy,” said Murthy, who presented on updates in CAR T-cell therapy in LBCL at an OncLive^® State of the Science Summit™ on hematologic malignancies.

In an interview with OncLive, Murthy, a hematologist/oncologist and physician at Mayo Clinic in Jacksonville, Florida, emphasized the importance of an accelerated manufacturing process for CAR T-cell therapy, discussed the use of CAR T-cell therapy in older and frail patients, and highlighted toxicity management strategies that have implemented and are under evaluation for patients receiving CAR T-cell therapy.

OncLive: Could you expand on the accelerated manufacturing processes of CAR T-cell therapies that are being evaluated for patients with LBCL?

Murthy: The accelerated manufacturing processes for an autologous CAR T product [rapcabtagene autoleucel (YTB323)] was recently published by Michael J. Dickinson, MBBS, DMedSc, [of Peter MacCallum Cancer Centre in Melbourne, Australia].1 We know that one of the barriers to patients receiving CAR T-cell therapy for LBCL is successful manufacturing and the time needed to manufacture [these therapies]. In this sense, patients will often need bridging therapy; sometimes, patients may not have that kind of time. Therefore, anything we can do to improve that [manufacturing] time and have more readily available products [is important].

We have seen trials with allogeneic CAR T-cell therapies; however, [this example of accelerated manufacturing] is a process where you can complete manufacturing within 48 hours and potentially get the product to patients within 5 days. The process itself, due to the short time of manufacturing, preserves the T-cell stemness, which will potentially have better efficacy.

An initial phase 1 study [NCT03960840] was promising, and we know that other manufacturers are also looking at their own accelerated process for autologous CAR T-cell therapies. There is certainly a bright future in that sphere.

How is CAR T-cell therapy used in patients who are frail or older?

We have seen some registry studies, including a large one from Germany, which showed that there was not [a significant] difference in [the rate of] cytokine release syndrome [CRS] based on age, although older patients had more immune effector cell–associated neurotoxicity syndrome [ICANS].²

There was the open-label, phase 2 [ALYCANTE trial (NCT04531046)] of axicabtagene ciloleucel [axi-cel; Yescarta], which [enrolled] patients who were considered ineligible for autologous stem cell transplant [ASCT], and they were treated with CAR T-cell therapy. This was an interesting study, because the definition of ineligibility for ASCT was based on age, receiving with a prior ASCT, and having an Hematopoietic Cell Transplantation–specific Comorbidity Index score of [at least] 3.³

Many transplanters, given the low risk of mortality in ASCT, may not consider this a transplant-ineligible patient [population]. However, there were plenty of other exclusion criteria [for this study] that would have made a patient ineligible for transplant, including some pulmonary compromise, cardiac [conditions], pleural effusions, and even hepatitis. These things, which would have made a patient truly ineligible for an ASCT, made them ineligible for this trial.

The treatment-related mortality in this trial was [9.7%], whereas a treatment-related mortality on average for an ASCT is about 1% to 2%. [ALYCANTE] is an intriguing study, but the notion to take away from this is we are still learning how to define which patients are ineligible for CAR T-cell therapy. We don’t know that yet. However, the studies are there to try to learn about better patient selection.

What toxicity management strategies are implemented when utilizing CAR T-cell therapies?

Another topic we discussed is toxicity management, and more importantly, toxicity prevention. We know that during the initial [phase 1/2 ZUMA-1 trial (NCT02348216)] with axi-cel, we had patients who were treated on cohort 6 who received prophylactic corticosteroids before axi-cel. There wasn't any change in efficacy, but patients experienced less severe toxicity and received less corticosteroids [vs those in other cohorts who received corticosteroids after axi-cel]. Now, how do we improve upon that?

There are recent studies to have looked at anakinra [Kineret] as a prophylactic strategy. There was a [phase 2] trial [NCT04148430] published by Jae Park, MD, and colleagues at Memorial Sloan Kettering Cancer Center, showing that anakinra prophylaxis was effective in reducing all-grade CRS and ICANS.⁴

Other strategies that we can use include next-generation sequencing [NGS], which can help predict CAR T-cell toxicity. A few studies, including a study we conducted out of the Mayo Clinic, showed that NGS findings could be predictive for the development of secondary malignancies. These are ways we are learning how to refine how to make CAR T-cell therapy for DLBCL safer and more accessible.

Could you highlight novel approaches to CAR T-cell therapy that are being investigated for patients with relapsed/refractory LBCL?

We didn't spend a lot of time discussing allogeneic CAR T-cell therapies and CAR natural killer–cell therapies, but there certainly is a lot in that space about feasibility and efficacy. This is a big question when we're comparing allogenic products to autologous products, and maybe [allogenic products] could be proven obsolete if these faster manufacturing processes for autologous products are effective enough.

The whole point of an allogenic CAR T-cell therapy was to get similar efficacy with a faster, off-the-shelf time. However, if we have autologous products with a faster manufacturing time, it puts the onus on all these allogenic products to be better than autologous products, which I don't think has been the case thus far in some of the early phase trials.

There have been some interesting things in terms of newer approaches, including dual-target CAR T-cell therapies, such as CD19- and CD20-targeted CAR T-cell therapies. The University of California, Los Angeles just published [findings from] their initial phase 1 study [NCT04007029], which had a very high response rate and complete response rate.5

At the Mayo Clinic, we are launching a phase 1 study of an alternate target to CD19 called B-cell activating factor receptor [BAFF-R], and this would be effective if patients were to relapse by antigen escape. Therefore, we need to have a different target to combat refractory lymphoma. We hope to launch this trial at the end of 2023.

There still are a significant number of patients who progress or do not respond to CD19-targeted CAR T-cell therapy. We need alternate therapies and alternate targets to reach those patients who may not have achieved a first remission with CD19-targeted CAR T-cell therapy and need an alternative therapy.

References

1. Dickinson MJ, Barba P, Jäger U, et al. A novel autologous CAR-T therapy, YTB323, with preserved T-cell stemness shows enhanced CAR T-cell efficacy in preclinical and early clinical development. Cancer Discov. 2023;13(9):1982-1997. doi:10.1158/2159-8290.CD-22-1276
2. Dreger P, Holtick U, Subklewe M, et al. Impact of age on outcome of CAR-T cell therapies for large B-cell lymphoma: the GLA/DRST experience. Bone Marrow Transplant. 2023;58(2):229-232. doi:10.1038/s41409-022-01867-4
3. Houot R, Bachy E, Cartron G, et al. Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial. Nat Med. Published online September 14, 2023. doi:10.1038/s41591-023-02572-5
4. Park JH, Nath K, Devlin SM, et al. CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results. Nat Med. 2023;29(7):1710-1717. doi:10.1038/s41591-023-02404-6
5. Larson SM, Walthers CM, Ji B, et al. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma. Cancer Discov. 2023;13(3):580-597. doi:10.1158/2159-8290.CD-22-0964