Balancing Cures and Complications With CAR T-Cell Therapy

Microscopic image of CAR T cells - Generated with Google Gemini AI

Chimeric antigen receptor (CAR) T-cell therapy, a revolutionary treatment for certain hematologic malignancies, has shown remarkable success but also carries significant risks. While this therapy can effectively target and destroy cancer cells, it can also trigger severe adverse effects (AEs) like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These AEs can be life threatening and require close monitoring and immediate intervention.

However, treatment paradigms have been evolving since CAR T’s introduction to the market in 2017, and many physicians and researchers wonder if certain guidelines can be changed to provide better quality-of-life to patients and their caregivers.

CAR T-Cell Therapy: “Not an Innocuous Therapy”

As CAR T-cell therapy is not an approved first-line treatment, patients referred to a CAR T center will have typically already undergone prior chemotherapy. Before starting therapy, patients must complete a series of appointments and evaluations before leukapheresis, manufacturing, and commencement of treatment.

William Wesson, MD

“[CAR T] has its own set of [adverse] effects. It is not an innocuous therapy,” said William Wesson, MD, Division of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Cancer Center, in an interview with Targeted Oncology^TM.

In Wesson’s words, “The whole idea of CAR T is that we are giving the immune system eyes where it was previously blind to the cancer. With that, we see activation of the immune system, often like it has never been activated before. We are waiting and expecting to see symptoms of activation of that immune system, which would be typical inflammation.” Most commonly, these symptoms of activation would be fever, body aches, and fatigue—not dissimilar to typical flu-like symptoms.

However, some patients experience more severe symptoms following CAR T.

CRS is caused by a rapid release of cytokines into the blood from the immune cells affected by an immunotherapy like CAR T. Signs of CRS include fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing.¹

Tocilizumab (Actemra) is a treatment for CRS, and the FDA’s risk evaluation and mitigation strategies (REMS) for CAR T-cell therapy require facilities administering CAR T to have at least 2 doses of tocilizumab onsite for each patient for immediate administration.² It is estimated that 1% to 23% of patients experienced grade 3 or 4 CRS; most cases are mild.³

Another of the concerning acute AEs following CAR T is ICANS.

“What is so unique and fantastic about CAR T is that it is a smart therapy. It can follow the cancer into the central nervous system, where many drugs cannot. The trick to that is that we are intentionally inducing inflammation, because we are activating the immune system,” said Wesson. “[But] when we have inflammation, we have signs of swelling, and swelling in the brain is a very dangerous thing.”

Historically, an estimated 20% to 70% of patients experience ICANS, and the condition is one that is relatively unique to CAR T. Risk factors include younger age, preexisting neurological conditions, high tumor burden, high intensity lymphodepletion, cytopenia, and early and/or severe CRS, although ICANS does not necessarily occur only in the context of CRS. ICANS can present as confusion, headache, attention deficits, aphasia, or encephalopathy developing to cerebral edema, coma, or seizures.⁴

However, both CRS and ICANS tend to develop shortly after CAR T-cell infusion. CRS can develop within 1 to 14 days³ and ICANS on an average of 5 days.⁴ Additionally, mitigation strategies have improved since CAR T’s inception.

Nausheen Ahmed, MD

“Back in 2017, [CRS and ICANS] were the 2 main [adverse] effects that were concerning when CAR T was first released. Over the years, we have better management of the [adverse] effects,” said Nausheen Ahmed, MD, associate professor of hematologic malignancies and cellular therapeutics at the University of Kansas Medical Center, in an interview with Targeted Oncology^TM.

FDA’s REMS Mandates and Considering New Monitoring Strategies

Ahmed and Wesson collaborated on 2 multicenter studies looking at optimizing the post-CAR T monitoring time in patients with lymphoma and multiple myeloma. Currently, the FDA requires patients receiving CAR T to stay close to the treatment center for 4 weeks after infusion to monitor for and manage potential incidences of CRS, ICANS, or other serious AEs. While this requirement ensures patient safety, it can create significant barriers to accessing this treatment, especially for patients with financial limitations or those living far from treatment centers.

The exact distance patients must be from the treatment center varies by institutions; Ahmed said that some centers want patients to be within 30, 45, or 60 minutes, and Wesson added that, at the University of Kansas, where he and Ahmed are located, patients who live over 30 minutes away from Kansas City have to relocate for the duration of treatment. Patients will often have to relocate before treatment begins to undergo any required testing, leukapheresis, and potentially bridging chemotherapy before CAR T infusion.

“This is a significant amount of time, a significant cost, all which goes to the patient and impacts their quality of life,” said Wesson.

“Only 30% of patients and actually live within 30 minutes of some centers, which basically means that a vast majority of patients have to relocate with their caregiver in order to get [CAR T],” added Ahmed. “There are many things that are not covered by insurance…There are patient assistance programs, but those also would not have 100% coverage. There are many out-of-pocket costs that are associated, which add up.”

Microscopic photorealistic image of CAR T cells - Generated with Google Gemini AI

In the study published in Blood Advances looking at 475 patients undergoing CAR T-cell therapy with axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi) for the treatment of lymphoma, findings suggested that the risk of new-onset CRS and ICANS was rare after 2 weeks following CAR T infusion, with 0% of patients experiencing CRS and 0.7% experiencing ICANS after 2 weeks. A single case of ICANS was reported in the third week following infusion. Here, 60% of patients (n = 285) experienced any-grade CRS, with a median onset of 3 days (IQR, 1-4). For ICANS, 32.4% of patients (n = 154) experienced any-grade ICANS, with a median time to onset of 4 days (IQR, 4-7).After the first 2 weeks, infections became the leading cause of nonrelapse mortality among these patients.⁵

A similar study looking at 129 patients with multiple myeloma receiving idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) was published in Transplantation and Cellular Therapy. Similar findings were reported: 0% and 1.6% experienced CRS and ICANS after 2 weeks following CAR T-cell infusion, and nonrelapse mortality was driven by hemophagocytic lymphohistiocytosis and infections through day +29, and then by infections through 3 months post-CAR T.

In total, 80% of patients (n = 103) had any-grade CRS with a median onset of 1 day (IQR, 1-6) and a median duration of 1 day (IQR, 0-2), and 26% of patients (n = 33) had any-grade ICANS with a median onset of 2 days (IQR, 1-6) and a median duration of 1 day (IQR, 0-7).⁶

“In all of those situations [where CRS and ICANS occurred after 2 weeks], there were extenuating circumstances, infections that kind of predisposed us to worse outcomes,” Wesson explained.

Based on these findings, the authors proposed a more flexible approach to monitoring CRS and ICANS after CAR T-cell therapy. They argue that the current 4-week monitoring period mandated by the FDA might be unnecessarily long and could be replaced with a more dynamic approach that focuses on individual patient needs and risk factors. Additionally, the study suggests that increased focus on preventing and managing infections could improve patient outcomes after CAR T-cell therapy.

“I do think that the first 2 weeks, [patients] should be monitored in a place where there is an infrastructure where they can get into intensive care treatment promptly. [But] there's no magical 4 weeks, right? There is still morbidity, there is still mortality from infections, even up to the 90-day mark,” Ahmed said.

Individualized Patient Approaches and Increasing Access to Care

Ahmed and Wesson agree that there is no single monitoring timeframe that makes sense for every patient undergoing CAR T, and while 4 weeks should not necessarily be a universal standard, some patients may require close monitoring for that long. Patients with a strong support system and referring oncologists who have robust infrastructure to monitor patients after CAR T may be able to go home earlier. There must be close communication between treatment centers and a patient’s local oncologist.

“I think it has to be a continuum,” Ahmed said. “I emphasize a flexible monitoring period, or whenever it is determined between the treatment center and the referring oncologist that the patient is now stable to be back at the infrastructure in the community. That is when the transition would be ideal, and that could be that could be at any time point.”

“I find, overwhelmingly, that when we send patients home, those oncologists are excited to learn about what [adverse] effects to look for, what to expect, [and] how to manage [patients],” said Wesson. “I think that the expectation that we could send patients home earlier with excellent peer hand-off would be exciting for both the treatment centers as well as the local oncologists, who would be able to welcome their patients back into their communities.”

For Ahmed, the biggest benefit of a flexible monitoring period is the increased access to potentially lifesaving therapy. By opting for a flexible monitoring period, the financial and practical burdens for patients and their caregivers would be lessened, making the treatment more available for patients who do not already live in the immediate vicinity of a CAR T center.

Ahmed also sees a future where CAR T-cell therapy can be even more accessible.

“I think that in general, the closer that CAR T can be to an off-the-shelf medication, the less the physical burden, the less the financial burden on the patient, that will increase the utilization of CAR T,” said Ahmed. “I wonder if some of those processes can be streamlined, which would be more on the scientific end, or if we have allogeneic products, that might make it easier. If we have products with even more safety profile where the monitoring period could be even more amenable where the patients can go back to the community earlier, that is what I am looking forward to.”

REFERENCES:

1. Cytokine release syndrome. National Cancer Institute. Accessed August 21, 2024. https://tinyurl.com/2k4xxp2p

2. Approved risk evaluation and mitigation strategies (REMS). FDA. Updated May 30, 2024. Accessed August 21, 2024. https://tinyurl.com/y4a94v8w

3. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56. Published 2018 Jun 15. doi:10.1186/s40425-018-0343-9

4. Sterner RC and Sterner RM. Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy. Front Immunol. 2022;13. doi: 10.3389/fimmu.2022.879608

5. Ahmed N, Wesson W, Lufti F, et al. Optimizing the post-CAR T monitoring period for axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Blood Adv. Published online July 23, 2024. doi:10.1182/bloodadvances.2023012549

6. Wesson W, Dima D, Suleman N, et al. Timing of toxicities and non-relapse mortality following car t therapy in myeloma. Transplant Cell Ther. Published online June 11, 2024. doi:10.1016/j.jtct.2024.06.012