CAR T-Cell Therapy Innovations Unfold Across the Spectrum of Cancer Care

Martin E. Gutierrez, MD

The expansion of CAR T-cell therapy across the landscape of hematologic malignancies has been propelled by continual improvements in the efficacy, safety, and logistics associated with offering this treatment. The benefits of this therapeutic strategy are also beginning to translate to patients with solid tumors, according to Martin E. Gutierrez, MD, and Lori A. Leslie, MD.

“It’s increasingly important to figure out how we can make this cutting-edge advancement in lymphomas, and soon to be many other cancers, available across many centers in the United States, so more patients have access,” Leslie said in an interview with OncLive^®.

“There is an exponential identification of targets for both T-cell engagers and CAR T cells that allows new clinical trials in different diseases at this moment,” Gutierrez added in the interview.

Lori A. Leslie, M

In the interview, Gutierrez and Leslie discussed common barriers to implementing CAR T-cell therapy programs, early successes that John Theurer Cancer Center in New Jersey has seen with outpatient CAR T-cell therapy administration, and developments on the horizon for administering this approach in solid tumors.

Gutierrez is the director of the Drug Discovery/Phase I Program, co-chief of Thoracic Oncology at John Theurer Cancer Center, Hackensack University Medical Center, as well as a professor in the Department of Oncology at Hackensack Meridian School of Medicine, both in New Jersey. He is also an associate member of the Thoracic & Gastrointestinal Oncology Program, co-chair of the Phase I Diseases Group, and co-chair of the Protocol Review and Monitoring Committee at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. Leslie is the director of the Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs at John Theurer Cancer Center, Hackensack University Medical Center, as well as an assistant professor at Hackensack Meridian School of Medicine.

OncLive: What are some common reasons why hospitals avoid implementing CAR T-cell therapy programs?

Leslie: CAR T-cell therapy is a completely different type of therapy than we have historically used in oncology. The [therapeutic] backbone used to be [treatments] like chemotherapy and targeted medications, and CAR T-cell therapy is a form of immune therapy. It’s a cell therapy. It harnesses the patient’s own immune system and is a living drug.

Because of that, regulatory [factors] need to be in place, and a framework needs to be in place to administer CAR T-cell therapy. There needs to be education for all providers who might encounter these patients to know how to manage both acute and longer-term adverse effects or toxicities, particularly cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. [Oncologists] need specialized training, and that could be a barrier as to why some centers may not [offer] CAR T-cell therapy.

However, as we’ve had CAR T-cell therapy available, at least as standard of care [SOC] for lymphomas, [where it was] first approved in 2017, we’ve learned how to manage CAR T-cell therapy. We intervene earlier to treat or prevent these toxicities. [This has] become routine at John Theurer Cancer Center and many CAR T-cell therapy centers. [CAR T-cell therapy is] being expanded throughout lymphomas, including aggressive lymphomas and indolent lymphomas, and it’s moving up in our treatment landscape.

What has been the process of implementing CAR T-cell therapy programs at John Theurer Cancer Center, and what successes have been seen?

Leslie: We’ve implemented CAR T-cell therapy at John Theurer Cancer Center in stages. We were involved in many of the clinical trials that led to approvals of CAR T-cell therapies. We had much experience [with CAR T-cell therapy] even prior to the initial FDA approval [of tisagenlecleucel (Kymriah) in patients with acute lymphoblastic leukemia in 2017].

[CAR T-cell therapy is] under our cell therapy division. We’re a large transplantation center. Volume-wise, [we are] 1 of the largest in the country, so it was easier, regarding the framework needed, to fold CAR T-cell therapy under that cellular therapy umbrella. The way it works here is that many patients are cared for by disease-specific providers. For example, I’m a lymphoma doctor. Then, once [patients] are admitted for the CAR T-cell therapy process, they’re part of our cell therapy team on the cell therapy floor.

One misconception that many centers may have about CAR T-cell therapy is the type of patient who is appropriate for CAR T-cell therapy. When we first were starting the program and doing clinical trials, the eligibility [criteria] for [a patient who] might be considered for CAR T-cell therapy was similar to what we use for autologous stem cell transplant [ASCT]. The age cutoff was approximately 65 years. Fit, older patients up to approximately 80 years without comorbidities are occasionally considered for ASCT. [However, we were mostly looking for] younger patients. They needed to have either no comorbid conditions or well-controlled, minimal comorbid conditions to be considered.

As we’ve rolled out our CAR T-cell therapy program and gotten experience with CAR T-cell therapy at our center and throughout the country, we’ve gotten more comfortable with treating patients who may be older and less fit. Many clinical studies do not have an upper age limit for CAR T-cell therapy. Geriatric CAR T-cell therapy is common these days across CAR T-cell therapy centers. [We have administered CAR T-cell therapy in] patients with comorbidities such as end-stage renal disease on dialysis, pacemakers, and inherited cardiomyopathy and an ejection fraction of less than 20% that’s well compensated. In many studies now, patients who are not fit and have an ECOG performance status of 2 are eligible for and are considered potentially appropriate for CAR T-cell therapy.

One of our other main points has been trying to spread awareness and education. Many times, people are pleasantly surprised at the type of patient who is a candidate for CAR T-cell therapy. It’s a one-and-done treatment. Once the patients get whatever bridging they need and get their CAR T-cell therapy, there’s hope for treatment-free observation that can be long lasting, potentially forever. It’s [a therapy] to strongly consider for a variety of patients.

Gutierrez: Regarding our strengths in cell therapeutics, we [conduct] approximately 400 to 600 transplants each year. We have a fantastic team, which has allowed us, on the SOC side and on the research side, to expand our portfolios.

What strides has John Theurer Cancer Center made toward offering CAR T-cell therapy in outpatient clinical trials?

Leslie: The Lymphoma Division [of the] John Theurer Cancer Center has been involved with CAR T-cell therapy since the beginning. [We were] involved in the initial studies that led to [the FDA approval of CAR T-cell therapy] in third-line large-cell lymphoma. Given how effective that was, then we were involved in the pivotal study comparing CAR T-cell therapy with SOC high-dose chemotherapy and ASCT, which showed that CAR T-cell therapy improved progression-free survival and overall survival in patients with high-risk, relapsed diffuse large B-cell lymphoma.

Much of this happened during the COVID-19 pandemic, when it was more complex to do [CAR T-cell therapy in an outpatient setting because patients might] develop a fever. However, now that that’s a little better controlled, we are involved in studies that formally investigate CAR T-cell therapy in the outpatient setting, without having patients admitted to the hospital for approximately 10 days to receive their treatment.

The success, safety, and efficacy of these studies has helped us want to be involved in efforts to bring CAR T-cell therapy [to the] outpatient [setting]. Once that is more widely available, it may make the opportunity to start a CAR T-cell program a bit more realistic for some centers that maybe would have a harder time [administering CAR T-cell therapy to] all these patients in the hospital. These studies have been so successful from a research perspective that we’re also involved in clinical studies looking at CAR T-cell therapy in frontline large-cell lymphoma. [CAR T-cell therapy] doesn’t only apply to large B-cell lymphoma; we also have approvals in follicular lymphoma. We’re also investigating that in earlier settings. [CAR T-cell therapy in] marginal zone lymphoma is being investigated further. [CAR T-cell therapy is approved in] mantle cell lymphoma. The more approvals we have, and the earlier CAR T-cell therapy shifts into the treatment landscape of lymphomas, it’s important to make it a bit more flexible logistically, so a wider range of patients who are eligible will have access to the treatment.

How has CAR T-cell therapy begun to make its way into the solid tumor arena, and what is the rationale for this shift?

Gutierrez: The rationale starts with immunotherapy. Immunotherapy has changed the landscape in solid tumors. We started [to study CAR T-cell therapy in solid tumors] back before 2012. With the approvals of checkpoint inhibitors, there has been a tremendous effort to continue developing different immunotherapy maneuvers to treat [patients with] solid tumors. CAR T-cell therapy and T-cell engagers are in that category of therapeutic interventions.

[Regarding successes], we are behind compared with [that in] hematologic malignancies. However, the identification of different targets and CAR T cells has been implemented in clinical trials across different diseases, [for example], HER2-positive diseases, PSMA-positive prostate cancer, and pancreatic cancer. Another target is Claudin 18.2 [CLDN18.2], which [is expressed in] many patients with gastric cancer. [At John Theurer Cancer Center], we have participated in at least 3 studies [evaluating CAR T cells in solid tumors]. One targeted HER2, the second targeted PSMA, the third targeted CLDN18.2, and hopefully another one is coming soon.

What does the future of CAR T-cell therapy at John Theurer Cancer Center look like?

Leslie: In hematologic malignancies, CAR T-cell therapy is expanding beyond lymphomas quickly. CD19 has been the target of all the approved CAR T-cell therapies thus far in lymphoma. Investigating other targets and mechanisms of resistance is the focus of many of our studies right now. Although CAR T-cell therapy is effective for many patients, it’s not an answer for all patients. How do we identify patients who will not have a long-lasting complete remission after CAR T-cell therapy? Is there something we can do earlier, such as [evaluating] cell-free DNA or liquid biopsy, to help identify patients who are unlikely to have a long-term benefit, and add [a consolidation treatment], whether that’s bispecific T-cell engagers or another agent, to fine tune and have more patients achieve that potential cure?

Gutierrez: From the solid tumor perspective, in terms of the development [of CAR T-cell therapy], we are following the hematology science. We have seen a significant increase in target identification in CAR T-cell development in solid tumors with different diseases across the board. We expect that in the next year or 2, [there will be] an exponential increase in new clinical trials that we will open and offer to our population based on the new technology that is being seen in solid tumors.

What advice do you have for academic and community colleagues regarding overcoming barriers associated with implementing CAR T-cell therapy programs?

Leslie: Reasonably, not every center can be a CAR T-cell center. It takes many resources. However, the more CAR T-cell therapies there are, the more accessible it is to have patients referred, and it’s important for these patients to be evaluated early. Keep CAR T-cell therapy in mind as something that might be [a] potential [treatment] for a patient and make sure early referrals are provided.

Our practice [at John Theurer Cancer Center] is that when I get a call about a patient who potentially needs CAR T-cell therapy, we bring them in the same day or the next day, because it’s not an immediate [process]. We need to get insurance approval, collect the cells, and manufacture [the CAR T cells]. Any points in that where you can minimize the wait time, [such as through] early referral, early identification, and telemedicine in areas that aren’t as densely populated as New Jersey, are opportunities to get the patients’ feet in the door earlier, so we can minimize any of that unnecessary wait. [That way, we can] make sure we get them to CAR T-cell therapy at the best time possible in their disease course and with the shortest wait time, [reducing the time in which they might] decompensate while waiting.

Gutierrez: From a solid tumor perspective, I would like to highlight the effort and resources needed. [These] clinical trials are quite intensive. [At John Theurer Cancer Center], we are fortunate because we have 2 large teams that [collaborate] to be able to execute [these trials]. On 1 side, I have the support of our bone marrow transplant cell therapeutics team, from apheresis to inpatient admissions. On the other side, I have the developmental therapeutics team and [members from] our Phase I program, who [work] together for logistics and implementation. It requires a huge amount of effort for an institution to open and execute these type of studies, but this is clearly necessary to continue to provide the next level of care to patients.