Many Challenges, Opportunities for CAR T-Cell Therapies in Lymphoma

Sattva S. Neelapu, MD

It’s been 5 years since the FDA approved the first chimeric antigen receptor (CAR) T-cell therapy to treat patients with previously treated lymphoma; yet, in many ways, the therapy is still in its early stages.¹ “It’s far better than autologous stem cell transplantation,” said Sattva S. Neelapu, MD, professor and deputy department chair, Department of Lymphoma/Myeloma, of The University of Texas MD Anderson Cancer Center in Houston. “It’s offering hope for patients who previously did not have any other options and had a median survival of [approximately] 6 months.”

However, Neelapu said the therapy has not reached its full potential, neither in terms of the underlying technology nor its uptake among eligible patients. “There’s still a lot of room for improvement,” he said.

Neelapu will discuss the use of CAR T-cell therapies in lymphoma during a presentation on September 30, 2022, at 1:02 pm during the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022) in Houston, Texas. His talk, “CAR-T in Lymphoma Future Directions: Targets, Resistance, and Persistence,” will include some of the latest CAR T–related trial results, as well as a discussion of how best to optimize cell therapy.

Growing Armamentarium of CD19-Targeted Therapies

Axicabtagene ciloleucel (Yescarta) was the first CAR T-cell therapy approved for lymphoma but was quickly followed by similar therapies.² “Currently, there are 4 different CAR products that have been FDA approved for lymphoma,” Neelapu said. “All of them target CD19.”³

Three of those products are approved to treat large B-cell lymphoma. In addition to axicabtagene ciloleucel (axi-cel), the FDA also approved lisocabtagene maraleucel (Breyanzi) and tisagenlecleucel (Kymriah) for certain patients with B-cell lymphoma,^4,5 as well as brexucabtagene autoleucel (Tecartus) for relapsed or refractory mantle cell lymphoma.⁶ In addition, axi-cel and tisagenlecleucel are also approved for follicular lymphoma. Neelapu said those approvals mean that a large number of patients are eligible for CAR T-cell therapy, but the existing data suggest the therapy will often be ineffective over the long term in the majority of patients. Only approximately 4 in 10 patients achieve long-term remission with CAR T therapies, Neelapu said.

What makes matters even more perplexing, he said, is that the treatment’s long-term remission rate remains at approximately 40%, even when it is moved up into the second line of therapy rather than the third.⁷ “We generally expect that when we move to earlier lines, we see a better outcome,” Neelapu said. “But that was not the case.”

Although the results still outperformed the standard-of-care treatment with salvage chemotherapy followed by autologous stem cell transplantation, Neelapu said there is scope for further enhancement. Moreover, despite the fact that CAR T-cell therapies have been available for 5 years, their uptake in the commercial setting has remained relatively low.

Barriers to Access

Neelapu estimates there are perhaps 10,000 individuals with B-cell lymphoma in the United States who would qualify for CAR T-cell therapy each year. However, he estimates that only approximately 20% to 25% of those who are eligible are getting the treatment. There are multiple possible reasons for the relatively low eligibility-to-uptake ratio—one being access. Neelapu said there are approximately 120 centers in the US that can provide the therapy, which averages to just 2 or 3 centers per state.

“It’s not nearly enough,” he said. “It requires patients to travel to another center and stay locally for a period of at least 5 to 6 weeks—along with the caregivers—to be able to get the treatment, so it is not practical for everyone.”

In addition, the fact that the current CAR T-cell products are autologous means each product has to be custom made for a specific patient from the patient’s own T cells, which increases both the cost of the therapy and the wait time. In a best case scenario, Neelapu said it can take 5 weeks for a patient to receive the product from the time a need has been identified.

“So [although] the existing products appear to be probably the most effective [therapies] available for large B-cell lymphoma, there are limitations and various things can be done to overcome those limitations,” he said. “That’s where I think the future is.”

Pushing Beyond CD19

In his SOHO 2022 presentation, Neelapu will delve into those efforts. One focus, he said, is overcoming mechanisms of resistance among the roughly 60% of patients who relapse after CAR T-cell therapy. Investigators are working on ways to design new CAR T-cell products that will be more effective in patients, with resistance to CD19-targeting products. Those strategies include targeting different antigens or changing the way the product is designed and manufactured.

“From a clinical development standpoint, post-CD19 CAR failures are the biggest unmet clinical need in large B-cell lymphoma,” he said. “In these patients, none of the existing treatments really work well.”

Neelapu said one issue is that approximately 30% of patients with diffuse large B-cell lymphoma are CD19 negative following treatment with axi-cel.8 “[This] means that if we target different antigens, [we] could potentially overcome that mechanism of resistance,” he said. “We are fortunate in B-cell lymphomas, because there are so many targets we can choose from.”

CD22

One of the most interesting potential targets is CD22, Neelapu said.A phase 1 trial (NCT04088890) published in 2021 showed that patients who were refractory to CD19 CAR T-cell therapy and then were treated with a new CD22-targeted product experienced improvement.⁹

“[Investigators] found a very high complete response rate, and a lot of them appear to be durable,” Neelapu said. “This is probably the most promising evidence that targeting a different molecule can be effective in the clinic in large B-cell lymphoma.” However, he also added that it’s not clear whether targeting CD22 will be more effective than other potential targets, such as CD20, CD79A, or CD79B. Those questions will require more research.

In the meantime, Neelapu said it may be wrong to think about the next step as choosing the best single target. “In the long term, we’d like to target multiple antigens at the same time,” he said. “And there are bispecific CARs and trispecific CARs that are in clinical trials now.”

Other Mechanisms of Resistance

Another suspected driver of resistance is suboptimal numbers of fit T-cells. Neelapu said experimental use of CAR T-cell therapies in a first-line setting led to the discovery that products derived from patients in an earlier line of therapy seem to lead to better results. “When we compared CAR T products in patients who were treated in the first line vs the third line, we found that the quality of the product was much better in terms of the T-cell phenotype and functionality,” he said.

In his presentation, Neelapu plans to review the ZUMA-12 trial (NCT03761056), a phase 2 trial that looked at axi-cel as part of first-line therapy in high-risk patients with large B-cell lymphoma. In that study, high-risk patients underwent 2 cycles of systemic chemotherapy. Patients who still had residual disease on a PET scan were then given an infusion of axi-cel. The study achieved an 89% objective response rate among the 40 patients treated. The response also appears to be durable; at 1 year, approximately three-quarters of patients were still in remission.¹⁰ “[This] is a lot higher than the 40% seen in second- and third-line settings,” he said.

Another strategy to improve the quality of CAR T-cell therapies is to optimize and accelerate the manufacturing of the therapies. For instance, Novartis has created a platform known as T-Charge, which dramatically speeds up the manufacturing process. YTB323 is a CD19-targeted CAR T product that uses the same design as tisagenlecleucel, but it is manufactured using a new, faster method.¹¹

“The production of CAR T cells used to require culturing the cells for [approximately] 10 to 14 days in the lab, but now with the T-Charge platform, it has been shortened to 2 days,” Neelapu said. “When they did that, they found that the function and the phenotype of the T cells [was] much better.”

A third apparent mechanism of resistance to CD19 CAR T-cell therapy is intrinsic tumor resistance. “[Essentially, for various reasons], the tumor cells resist CAR T–mediated killing,” he said.

Neelapu said several potential mechanisms for intrinsic resistance have already been identified, but strategies to overcome intrinsic resistance are still in the early phases of development. He expects to see significant progress in this area in the coming years. “We will probably uncover a lot more resistance mechanisms than what we currently know,” he said.

Autologous vs Allogeneic Products

If 1 major focus of CAR T development is centered around evading resistance, Neelapu said another key strategy is finding ways to use allogeneic cells instead of autologous cells to derive therapies. Using allogeneic cells can allow something like an “off-the-shelf” approach to CAR T-cell therapy, rather than the time-consuming process of making patient-specific doses. It would also allow manufacturers to make many more doses from a single donor and would likely significantly reduce the cost of the therapy. But there’s 1 key problem, Neelapu said. “The main hurdle we are seeing right now in some of these early studies is that these cells don’t persist as long in the body,” he said.

Although autologous CAR T cells can persist for years in the body, the current allogeneic products do not come close to that level of durability. “With allogeneic CAR T products, most of the time they persist in the body for only 1 or 2 months, because once the host immune system recovers in a patient, they reject these allogeneic cells,” Neelapu said.

The ALPHA-2 study (NCT04416984) of ALLO-501A (Allogene Therapeutics, Inc) is 1 attempt to solve that problem. “One approach taken by the Allogene product is that they knock out this molecule called CD52, which allows them to give a better conditioning regimen with anti-CD52 antibody on top of cyclophosphamide and fludarabine to induce this prolonged lymphodepletion in the patient,” he said. “That way, the rejection may be delayed.”¹²

Neelapu said many other approaches are currently being investigated or are soon to be the subjects of clinical trials. He thinks allogeneic therapies will likely win out over the long term. “They will likely be the future for cell therapies,” he said.

Insights for Community Oncologists

For community oncologists, Neelapu said chemotherapy remains the standard choice for first-line therapy for large B-cell lymphoma, as it cures 60% to 65% of patients. In the second-line setting CAR T therapy is now the standard of care. “If we ask the question, as a second line: What is the treatment that has the highest chance of achieving a cure in these patients? That’s CAR T,” he said.

As a practical matter, Neelapu said it is important for community oncologists to refer patients to a CAR T therapy center early, as there is some evidence that multiple prior therapies can diminish the effectiveness of autologous CAR T-cell products. “Early referral by the community oncologist at first relapse is key to achieve an optimal outcome and the best chance of cure,” he said.

In situations where economic or other barriers make it difficult for a patient to get treatment at a CAR T center, Neelapu said bispecific antibody therapies may soon be available. Such treatments could be a good bridging option, because unlike chemotherapy, they do not affect T-cell numbers or functions.

SOHO and the Return of In-Person Meetings

Reflecting on SOHO 2022 and the return to a fully in-person meetings, Neelapu said the virtual format necessitated by the COVID-19 pandemic had certain advantages. “I think Zoom has, in some ways, encouraged more people to attend,” he said. “And if it’s a live virtual presentation, we see a lot more people asking questions.”

However, he said he’s looking forward to something Zoom cannot provide. “With an in-person meeting, what’s appealing is to talk offline with colleagues and investigators from academia and industry,” he said. “[This] can generate a lot of interesting discussions, new ideas, and collaborations—that’s missing in a virtual meeting.”

_REFERENCES:

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_{4. Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel) significantly improves outcomes, showing superiority over 20-year standard of care in second-line relapsed or refractory large B-cell lymphoma based on TRANSFORM study results. News release. Bristol Myers Squibb; December 11, 2021. Accessed August 21, 2022. https://bit.ly/3CsOPK3}

_{5. Kymriah (tisagenlecleucel), first-in-class CAR-T therapy from Novartis, receives second FDA approval to treat appropriate r/r patients with large B-cell lymphoma. News release. Novartis; May 1, 2018. Accessed August 21, 2022. https://bit.ly/3QH1QUx}

_{6. U.S. FDA approves Kite’s Tecartus, the first and only CAR T treatment for relapsed or refractory mantle cell lymphoma. News release. Gilead Sciences, Inc; July 24, 2020. Accessed August 21, 2022. https://bit.ly/3PRDpT8}

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_{9. Frank MJ, Baird JH, Patel S, et al. CD22-CAR T-cell therapy mediates high durable remission rates in adults with large B-cell lymphoma who have relapsed after CD19-CAR T-cell therapy. Blood. 2021;138(suppl 1):741. doi:10.1182/blood-2021-152145}

_{10. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022 Apr;28(4):735-742}

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