Adam Sperling, MD, PhD

Instructor in Medicine

Harvard Medical School

Medical Oncologist

Dana-Farber Cancer Institute

Boston, MA

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment in the hematologic malignancy space, but it has a long way to go to effectively treat the many hematologic cancers. That is because it faces obstacles such as lengthy manufacturing time, patient access, adverse events, and variable efficacy.

Saad J. Kenderian, MB, ChB

Consultant

Division of Hematology

Department of Internal Medicine

Assistant Professor of Oncology

Assistant Professor of Immunology

Assistant Professor of Medicine

Mayo Clinic College of Medicine and Science

Rochester, MN

Researchers are working to optimize the outcomes associated with CAR T-cell therapy, focusing on unique combinations that may enhance T-cell fitness, improving tumor eradication and treatment outcomes. Much of this research is in the early stages. If successful, it will provide patients with additional treatment options and potential cures.

Challenges in Hematologic Malignancies

CAR T-cell therapy engineers the patient’s T cells in a manufacturing facility so they can target cell surface antigens to destroy the cancerous cells. Although CAR T-cell therapy shows major promise and has already positively impacted many patients with hematological malignancies, there are still many challenges to overcome.

“In multiple myeloma, the No. 1 challenge is that we still don’t have a curative therapy,” said Adam Sperling, MD, PhD, medical oncologist and instructor in medicine at Harvard Medical School and Dana-Farber Cancer Institute in Boston, Massachusetts, during an interview with Targeted Therapies in Oncology™. “How do we get more patients to respond? And then how do we make sure that those responses last longer and [patients] don’t relapse?” The same could be said for many other hematologic malignancies; this is a central driving force for researchers and clinicians. Combining CAR T Cells With Targeted Agents

There are currently 6 CAR T-cell products with FDA approval.¹ “CAR T cells are approved as a single- agent, single-infusion therapy,” said Sperling. “For the most part with the CAR T cells, they’re a one-and-done treatment and the patients are generally monitored thereafter. Increasingly, CAR T-cell therapies are being combined with other anticancer agents. For myeloma, combinations can include a standard myeloma therapy given after the CAR T-cell infusion as a maintenance strategy.

In myeloma, “I think the 2 things that are being tested with the approved [CAR T-cell] agents is moving them up into earlier lines to see if they work better in that setting and combining them with other therapies,” Sperling said.

Bruton Tyrosine Kinase Inhibitors

A number of phase 1 and 2 studies are combining CAR T cells with targeted therapies like Bruton tyrosine kinase (BTK) inhibitors. Researchers are combining acalabrutinib (Calquence), a BTK inhibitor, with axicabtagene ciloleucel (axi-cel; Yescarta), an anti-CD19 CAR-T cell therapy, to treat B-cell lymphomas such as follicular lymphoma (NCT04257578).² Another trial is evaluating acalabrutinib and anti-CD19 CAR T cells for relapsed/refractory mantle cell lymphoma (MCL; NCT04484012; FIGURE).³ A phase 3 study in China is researching whether BTK inhibitors ibrutinib (Imbruvica), zanubrutinib (Brukinsa), and orelabrutinib, which is not approved in the US, in combination with anti-CD19 CAR T cells are safe and effective in relapsed/refractory B-cell lymphomas (NCT05020392).⁴ Ibrutinib is approved for chronic lymphocytic leukemia (CLL), MCL, and several other diseases, said Saad J. Kenderian, MB, ChB, a hematologist and assistant professor of internal medicine, immunology, and oncology at Mayo Clinic College of Medicine and Science in Rochester, Minnesota.

“Ibrutinib works on the leukemic B cells, but also it works on T cells and favorably changes T cells from what we call the T_H2 phenotype, suppressive T cells to the T_H1 phenotype, which is the T cells that kill,” Kenderian told Targeted Therapies in Oncology. He added that early results of studies combining ibrutinib with CAR T cells are encouraging, with improvements in CAR T-cell function and (possibly) response.

BCMA

An exciting target in myeloma is B-cell maturation antigen (BCMA), said Sperling. He said a dual-specific CAR T-cell therapy has been developed that targets both BCMA and an antigen called GPRC5D, which is widely expressed on myeloma cells. In clinical trials, this therapy has shown high response rates “even in patients who are exposed to a BCMA-targeting agent prior to the GPRC5D-targeting cell therapy.” If, for example, only 98% of the cells express BCMA, the other 2% might lead to relapse. But if that 2% of cells expresses GPRC5D, combining both targeting agents can potentially eliminate all the cancer cells. Clinicians could give a BCMA-directed CAR T-cell product followed by an anti-GPRC5D bispecific antibody. He said that approach is being tested, with promising early results.⁵

Sperling noted that a study in China is looking at combination therapy directed at BCMA and CD19. “I think that’s an easy combination because we have [CAR T-cell therapies targeting both of those antigens]. Those are 2 targets that have been tested, 1 in lymphoma and 1 in myeloma. And we have a lot of experience with them, so they combined them.” He said CD19 is not a good target in multiple myeloma, so anti-CD19 treatments may not make sense for that patient population. The data are preliminary to determine whether the combination is better than therapies directed at either target alone. “I think it’s an interesting approach. I think that once we have multiple good targets in multiple myeloma or in lymphoma or leukemia, combining 2 of those together and hitting both at the same time may produce better outcomes.”

PI3K Inhibitors

Another class of targeted therapy being tested with CAR T cells is PI3K inhibitors. Results were recently published from a phase 1 study (NCT03274219) in multiple myeloma that used idecabtagene vicleucel (ide-cel; Abecma) cultured with the P13K inhibitor bb007 to enrich the drug product for memorylike T cells.⁶

Some combinations are being tested to decrease CAR T cell–associated toxicity and others are designed without reducing the activity or efficacy of the CAR T-cell therapy, said Kenderian. In CLL, the PI3Kδγ inhibitor duvelisib (Copiktra) is being evaluated for the prevention of cytokine release syndrome (as measured by IL-6 production) in preclinical models treated with CAR T cells. Duvelisib was shown to block CRS/ IL-6 production without reducing the activity of the CAR T cells.⁷

Checkpoint Inhibitors

CAR T cells can also be logically combined with checkpoint inhibitors, said Kenderian. “Checkpoint inhibitors overcome T-cell exhaustion. We think T-cell exhaustion plays a role in why T cells don’t work, so why not combine [CAR T cells with checkpoint inhibitors],” which may quickly invigorate the CAR T cells and increase the response rate, he asked. Studies are ongoing to explore this topic.^8-10

Stem Cell Transplant

Hematopoietic stem cell transplant (HSCT) is part of the standard of care for many hematological malignancies,¹¹ but it may one day be supplemented by or overtaken by CAR T-cell therapy. A recent systematic review and meta-analysis evaluated the efficacy and safety of consolidative HSCT after anti-CD19 CAR T-cell therapy in acute lymphoblastic leukemia. HSCT was found to prolong overall survival and reduce the risk of relapse compared with non-HSCT treatment.¹² A multicenter retrospective study evaluated allogeneic transplant following anti-CD19 CAR T-cell therapy for large B-cell lymphoma. According to results published in January 2023, HSCT after CAR T-cell failure was found to provide durable remissions in a subset of patients. Investigators reported that better outcomes were seen in patients who received fewer than 2 lines of therapy between CAR T-cell therapy and HSCT and those who were in complete response at the time of HSCT.¹³

Although CAR T-cell therapy is toxic, said Sperling, it is not quite as toxic as HSCT. Research into replacing HSCT with CAR T-cell therapy is important, but the current clinical trial landscape consists of standard 3- or 4-drug induction regimens, followed by transplant and then maintenance.

In those studies, Sperling said, the median progression-free survival (PFS) is 6 years or more. When designing a randomized study to replace HSCT with CAR T-cell therapy, “you’re talking about 10 years of follow-up, to read out. That’s a real challenge for the field.”

Development of CAR T Products

One big barrier to more widespread deployment of CAR T-cell treatments is the manufacturing process, which is time intensive and expensive. “In the best-case scenario, with the companies that have efficient manufacturing, it takes them 3 to 4 weeks,” said Kenderian. With myeloma, that can be even longer; he has seen bottlenecks and wait-lists of 2 months for the therapies. “Many of our patients [who] have cancer cannot wait; the cancer is progressing.”

In addition to manufacturing time, the patient needs insurance approvals, pretreatment testing, and scheduling of apheresis to capture the cells; these delays can extend the time to treatment by another month.

Kenderian said approximately a dozen academic institutions, including Mayo Clinic, are manufacturing CAR T-cell products in-house. This process takes 6 to 8 days, allowing patients to receive therapy more quickly and at one-tenth the standard manufacturing cost, he said. Off-the-shelf allogeneic CAR T cells are also being tested to decrease that time and cost.

Challenges to Optimal Outcomes

Several challenges can prevent patients from receiving optimal benefits from CAR T-cell treatment. Patients undergoing CAR T-cell therapy can develop unique toxicities, such as cytokine release syndrome and neurotoxicities. “They may end up in the intensive care unit and require frequent visits to hospitals, and at times, toxicity results in death,” said Kenderian.

Another barrier is the efficacy. Kenderian noted that among patients with lymphoma, about 70% to 80% respond initially, with 30% to 40% experiencing a durable response.¹ However, in multiple myeloma, the durable response rate is lower, Kenderian said.¹⁴

The first CAR T-cell therapy approved for multiple myeloma, said Sperling, was idecabtagene vicleucel.15 “The progression-free survival has been 8 to 12 months, depending on what study you look at,” Sperling said. For ciltacabtagene autoleucel (cilta-cel; Carvykti), which was approved next, PFS is longer but there are fewer real-world data. “We’re talking about a median progression-free survival of about 2 years. So that’s excellent, but 2 years is still a pretty short time.” He said researchers are trying to determine how to improve therapies to produce greater efficacy and deeper, more durable responses.

T-Cell Fitness

T-cell fitness also affects treatment efficacy, though currently there is no standard way to define or use it as a prognostic marker. Fitness refers to the T cell’s ability to generate a CAR-mediated immune response to help destroy malignant cells and provide a durable response.¹⁶

T-cell fitness can be impacted by a person’s age, disease burden, cancer treatment, and any chronic infections. “If my T cells are beaten up from chemotherapy and they are lousy [and are used] to make CAR T, most of the time the CAR T will be lousy, too,” said Kenderian.

The timing of T-cell collection during the disease course and treatment can affect the CAR T-cell product. As patients are exposed to more therapies, including alkylating agents, “there may also be an accumulation of damage to the T cells, and they sort of lose memory function and may be less efficacious at targeting myeloma cells,” said Sperling.

This has led to discussions about the optimal timing of T-cell collection. “Should we be collecting T cells in all patients at an early point, maybe at the time when we collect stem cells for autologous transplant? Or at another time, storing them and using them later when we need to?” Sperling asked. Moving T-cell collection to earlier in the course of disease could also impact T-cell fitness, Sperling said, “but we don’t have any real strong data that actually [show earlier collection] would improve outcomes.”

Tumor Microenvironment

The reason CAR T-cell therapy works better for some hematological malignancies is probably related to the tumor microenvironment, said Kenderian.

“Evolutionarily, [cancer cells] figure out ways to escape the immune system,” Kenderian said. The cancer develops its own immunosuppressive microenvironment, which suppresses the CAR T cells.

He said clinical trials in patients with solid tumors showed that when CAR T-cell therapy is given to patients with brain or lung cancer, followed by a biopsy of the tumor, CAR T cells are present.

“They manage to get to the tumor. But when you test them, you see that they are lousy; they’re suboptimal. They don’t work. The microenvironment has figured out ways to shut down the CAR T.”

The tumor microenvironment can dampen CAR T-cell efficacy to promote cancer cell survival and evade immune surveillance, including in hematological malignancies.¹

“We need to make the CAR T [cells] resistant to the tumor microenvironment,” Kenderian said. That can occur through combination with other therapies.

As to why CAR T-cell therapy works better for some hematological malignancies than others, “I think that’s the million-dollar question,” Sperling said. Some of it comes down to basic disease biology, he said. Lymphoma and leukemia have been curable with therapies like standard chemotherapy or transplant. Fewer patients with multiple myeloma are cured.

“We don’t totally understand where the cells are coming from when you get a relapse,” he said. “But there must be some way to eventually eradicate all of the myeloma cells.”

Conclusion

While researchers study whether CAR T-cell therapy can move into earlier lines of treatment, they are also looking for effective therapies to combine with CAR T cells. “The studies that have looked at CAR T cells are all very exciting. Despite the problems, they’re still producing very high response rates,” said Sperling. “I don’t want to take away from how life changing these therapies can be. But I think it’s a matter of improving what we have.”

With so many agents available, there is a strong rationale to combine them with CAR T cells, said Sperling. “I hope we will continue to see improved outcomes similar to what we’re seeing in the preclinical studies and we can improve on the successes of CAR T-cell therapy.” He said it is an exciting field, adding, “I think we will see more and more of these combinations in the clinic and, hopefully, approved.”

REFERENCES

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4. Autologous cells derived anti-CD19 CAR-engineered T cells with concurrent BTK inhibitor for B cell lymphoma. ClinicalTrials.gov. Updated October 21, 2021. Accessed September 25, 2023. http://bit.ly/3SzwP6W

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7. Amatya, P, Carter AJ, Ritchey JK, et al. The dual PI3Kδδ inhibitor duvelisib potently inhibits IL-6 production and cytokine release syndrome (CRS) while maintaining CAR-T function in vitro and in vivo. Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. http:// bit.ly/3ICZfZd

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