CAR T-Cell Therapy Remains Underutilized, Despite Improvements in Access

Significant advancements in chimeric antigen receptor (CAR) T-cell therapy have occurred over the past several years as successful clinical trials and FDA approvals have positively impacted patient outcomes. When the FDA approved the first CAR T-cell therapy, tisagenlecleucel (Kymriah), in 2017,¹ common toxicities occurring in more than 20% of patients were cytokine release syndrome (CRS), hypogammaglobulinemia, pyrexia, hypotension, and tachycardia. Grade 3 or 4 adverse events (AEs) were noted in 84% of patients. Further barriers included insurance access, location of treatment centers, and manufacturing turnaround for the CAR cells.

Now, 7 years later, how have these barriers been overcome? What can community oncologists do to optimize CAR T-cell therapy for their patients with cancer?

Delivery Model and Location for Care

Traditionally, the therapy has been delivered in large academic medical centers. This has generated 2 challenges: the patient’s geographical proximity to treatment and the costs associated with inpatient therapy.²

“I think one of the biggest challenges with CAR T-cell therapies is that there are relatively few sites throughout the US that can deliver these complex therapies,” Chijioke Nze, MD, told Targeted Therapies in Oncology during an interview. “There are about 311 sites that are FACT [Foundation for the Accreditation of Cellular Therapy] accredited that can deliver CAR T-cell therapies,” Nze continued.³

One report said that as many as 11 states do not have any medical centers that provide the treatment.⁴ Which states have the most CAR T-cell centers? California has 12, followed by New York, Texas, and Pennsylvania, with 10 centers each. Patients in rural areas of the US have very few sites where they can receive this treatment, resulting in many patients having to travel and relocate hundreds of miles from home, family, and work obligations just to receive cancer care.

“It’s a complicated therapy available in a limited number of sites,” Houston Holmes, MD, MBA, a clinical assistant professor of medicine at Texas A&M Health Science Center and director of hematology at Texas Oncology in Dallas, Texas, said during an interview with Targeted Therapies in Oncology. The procedure is resource intensive, and the sites that provide this care must be specially certified.

Other barriers include the cost, transportation, and lodging required to undergo the therapy. Identifying resources early on in the course of treatment is crucial, whether that involves contacting patient advocacy groups, such as the Lymphoma Research Foundation or the Leukemia & Lymphoma Society, or using a nurse navigator at the institution who can identify resources for transportation and housing. The American Cancer Society has a program called Hope Lodge that provides a free home away from home for patients with cancer and their caregivers, Holmes said.

Nze emphasized the importance of getting support for caregivers. “Many times we focus on the patient’s needs, but caregivers walk patients through this journey, making sure appointments are made,” Nze said.

Another factor to consider is the possible loss of income for both patient and caregiver, especially early on in treatment, as each undergoes these therapies. “It’s important to consider how treatment can affect earnings potential,” Nze continued.

Community-Based Setting

A potential solution that is being evaluated, and one that is receiving growing attention, is the possibility of delivering CAR T-cell therapy in community-based oncology clinics and hospitals. Additional training and resources would be required for the treatment to be administered but moving the setting from an academic medical center into the community would drastically improve and increase patient access.

A community setting would also alleviate some of the inpatient costs associated with traditional CAR T-cell therapy. Patients would still need ready access to the treatment center for weeks after treatment to be monitored for any adverse events that arise following CAR administration.

Trial data have shown that a significant number of patients treated in the outpatient setting require subsequent hospitalization, often related to life-threatening adverse effects, including CRS and immune effector cell–associated neurotoxicity syndrome.^5,6

In one study, Bachier and colleagues reported⁶ on patients with relapsed/refractory large B-cell non-Hodgkin lymphoma (NHL) who were treated with lisocabtagene maraleucel (liso-cel; Breyanzi) in the outpatient setting in TRANSCEND-NHL-001 (NCT02631044). Further, in two phase 2 studies assessing the safety and efficacy of liso-cel, patients received the drug as third-line or later therapy (TRANSCEND- OUTREACH-007; NCT03744676) or as treatment in the second line for patients not eligible for transplant (TRANSCEND- PILOT-017006; NCT03483103).⁵

After the procedure, patients had to have a caregiver for 30 days post infusion with liso-cel; receive safety-monitoring education, including how to recognize serious AEs such as fever; and stay within 1 hour’s travel time of the site of care.⁵

A subset of patients with relapsed/refractory large B-cell NHL was successfully treated with liso-cel and monitored for CAR T-cell–related toxicity in the outpatient setting, including elderly patients and patients with high tumor burden.⁵

Severe CRS and AEs occurred at a low incidence. The number of early hospitalizations was low, and 41% of patients did not require hospitalization in the first month post liso-cel infusion. Most patients (65%) achieved an objective response.⁵

Early Identification

One essential task for community oncologists is identifying patients for early referral to CAR treatment centers. “If you can identify a patient who seems like they might be refractory or a patient who might relapse, getting them into a center as soon as possible is important,” Nze said. “That really is step 1.”

Once oncologists have identified patients, determining their insurance eligibility is almost as important. “Referrals themselves can take a little bit of time,” Nze said. Noting in the patient chart that the patient meets the criteria for CAR T-cell therapy can be done early on and will get the prior authorization process started, he added.

“The sooner patients are able to get into these centers, the sooner the process of extracting the cells for proper manufacturing and processing can occur,” Nze said.

With aggressive disease, such as lymphoma, the timing to start the process is crucial, said Holmes. “As soon as you suspect relapse in a patient with large B-cell lymphoma, we would encourage referral to a cell therapy center, or at least have a conversation with the patient because the disease can progress rapidly,” Holmes said. “You don’t want to miss the opportunity for treatment with what could…be curative,” he continued.

Overcoming Toxicities

Acute toxicity following CAR T-cell therapy typically occurs in the first weeks following infusion. CRS, a systemic inflammatory condition, coincides with the expansion of CAR T cells due to the activated cells producing cytokines and amplifying activation of monocytes and macrophages that further produce pro- inflammatory cytokines. Current therapeutic strategies for managing CRS include the use of corticosteroids and the IL-6 receptor antagonist tocilizumab (Actemra) as first-line therapy.⁷ The TABLE⁷ provides a summary of treatments to treat CRS.

Manufacturing Challenge

CAR T-cell therapy is an intensive short- interval therapy. Patients prepare for it by undergoing lymphodepletion, and they receive chemotherapy or radiation as bridging therapy to help manage the cancer while the CAR T cells are manufactured. Initially, the turnaround time to manufacture CAR T cells was upwards of 3 weeks. Under typical conditions, the delivery of CAR T therapy is a complex process, requiring a well- orchestrated series of patient, caregiver, provider, and manufacturer roles. Hurdles at any stage of therapy delivery may affect patient access to treatment.⁸

The median time from leukapheresis to product delivery is 14 days for axicabtagene ciloleucel (axi-cel; Yescarta), 21 days for liso-cel, and 54 days for tisagenlecleucel.⁵ “There are a lot of companies…trying to reduce that manufacturing time and increase the capacity [to treat more patients],” Nze said. “The objective is to decrease the delays in treatment.”

Cost

Reimbursement restrictions can result in delayed access to this therapy. Estimates indicate that two-thirds of health plans restrict access to cellular therapies or gene therapy coverage, likely because of the high cost of treatment.⁹ Further clouding the therapy’s benefit is the use of surrogate markers, such as overall response rate or progression-free survival, which have been cited as a rationale for limiting access based on scientific uncertainty.⁹

Additionally, there is a disparity in reimbursement when comparing commercial insurer payments with Medicare payments to hospitals. Streamlining reimbursement mechanisms to ensure a more equitable payment schedule would encourage hospitals to provide the therapy. Equitable reimbursement could also improve hospital delivery and access for patients with Medicare Part B coverage, which begins at age 65 years—the median age for a multiple myeloma diagnosis.⁹

Alternatives

Several alternative cellular therapies are undergoing evaluation and have already reached the clinic. Nze is encouraged by the approvals for bispecific antibodies in hematologic malignancies, such as epcoritamab-bysp (Epkinly) or glofitamab-gxbm (Columvi) in relapsed/ refractory diffuse large B-cell lymphoma, and their evaluation in clinical trials for solid tumors, such as breast cancer (NCT02892123), and in research for inflammatory, autoimmune, and neurodegenerative diseases.

“Bispecific antibodies, typically the CD20 T-cell engagers, are an exciting technology,” Nze said. “These have been evaluated post CAR T [therapy] or in transplant-ineligible patients who might not meet the clinical criteria for transplant,” he continued. The most significant benefit these agents pose over CAR T-cell therapy is their off-the-shelf characteristics. “They’re accessible, they’re effective, and they are financially comparable. They could replace CAR T-cell therapy in certain populations.”

Another alternative undergoing evaluation is allogeneic CAR T-cell therapy, in which cells from healthy donors are used to create the CAR. “You can make many doses of the CAR from a single donor selection,” Holmes said.

Traditional CAR manufacturing relies on the autologous harvesting of cells from peripheral blood. However, the variability among patients caused by prior treatment and disease history can lead to inefficiencies in yield for the final product.

Allogeneic products are undergoing evaluation because of their ease of production and the potential for gene-editing technology.10 The improved turnaround “avoids the current manufacturing delay and apheresis,” Holmes said. “You skip a whole portion of the process that’s necessary with autologous CAR T cells.”

Early research has demonstrated proof of principle, early good responses, and encouraging toxicity data overall, said Holmes. “There is a huge array of strategies that are undergoing evaluation, and many look promising, but it’s still early, so determining which ones prove to be most effective and safe remains to be seen,” Holmes said.

Significant progress has been made since the approval of the first CAR T-cell therapy. Improved efficacy, turnaround time, and access have had an impact, but the therapy has been somewhat underutilized, and there is still tremendous room for improvement. “These cellular therapies can cure [some] patients, but it’s still just a [small number]. It makes enrollment in clinical trials hugely important,” said Holmes.

REFERENCES

1. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. Accessed June 23, 2024. https://tinyurl.com/4ypn423c

2. Gajra A, Zalenski A, Sannareddy A, Jeune-Smith Y, Kapinos K, Kansagra A. Barriers to chimeric antigen receptor T-cell (CAR-T) therapies in clinical practice. Pharmaceut Med. 2022;36(3):163-171. doi:10.1007/s40290-022-00428-w

3. Search for a FACT accredited organization. Foundation for the Accreditation of Cellular Therapy. Accessed June 18, 2024. https://accredited.factglobal.org/

4. Directory of CAR T-cell therapy centers. Blood & Marrow Transplant Information Network (BMT InfoNet). Accessed June 17, 2024. https://tinyurl.com/d2v3pnhu

5. Nze C, Flowers CR. Barriers to accessing cellular therapy for patients receiving care in community practices. Hematology Am Soc Hematol Educ Program. 2023;2023(1):382-385. doi:10.1182/hematology.2023000518

6. Bachier CR, Palomba ML, Abramson JS, et al. Outpatient treatment with lisocabtagene maraleucel (liso-cel) in three ongoing clinical studies in relapsed/refractory (r/r) B cell non-Hodgkin lymphoma (NHL), including second-line transplant ineligible patients: Transcend NHL 001, Outreach, and PILOT. Blood. 2019;134(suppl 1):2868. doi:10.1182/blood-2019-127566

7. Schuster SJ, Bishop MR, Tam C, et al. Sustained disease control for adult patients with relapsed or refractory diffuse large B-cell lymphoma: an updated analysis of Juliet, a global pivotal phase 2 trial of tisagenlecleucel. Blood. 2018;132(suppl 1):1684. doi:10.1182/blood-2018-99-115252

8. Bailey SR, Berger TR, Graham C, Larson RC, Maus MV. Four challenges to CAR T cells breaking the glass ceiling. Eur J Immunol. 2023;53(11):e2250039. doi:10.1002/eji.202250039

9. Mikhael J, Fowler J, Shah N. Chimeric antigen receptor T-cell therapies: barriers and solutions to access. JCO Oncol Pract. 2022;18(12):800-807. doi:10.1200/OP.22.00315

10. Lonez C, Breman E. Allogeneic CAR-T therapy technologies: has the promise been met? Cells. 2024;13(2):146. doi:10.3390/cells13020146