Although Promising, CAR T-Cell Therapy in T-ALL Carries Many Challenges

For patients with relapsed/ refractory T-cell acute lymphoblastic leukemia (T-ALL), limited curative options are available, and many patients will need to use multiple modalities to achieve remission.

According to Rayne Rouce, MD, chimeric antigen receptor (CAR) T cells are showing promise in this space. However, numerous challenges, including those related to manufacture, those that are patient/disease specific, and those regarding risk mitigation, remain a struggle.

Additionally, trials evaluating novel agents for refractory T-ALL are often difficult to perform. An unmet need remains for experts to address the barriers in this space at each step, including at trial conception and implementation and after trial accrual has begun.

During the 2023 American Society of Pediatric Hematology/Oncology Conference, Rouce discussed historical outcomes, treatment options, and strategies being explored for patients with T-ALL.¹ Rouce is assistant professor of pediatrics at Baylor College of Medicine and Texas Children’s Hospital, both in Houston.

Historical Outcomes and Options

According to Rouce, the only curative option for patients with relapsed/refractory T-ALL is an allogeneic stem cell transplant. However, experts typically juggle multiple options, including the standard salvage therapy, which could include an R3 (vincristine, mitoxantrone, dexamethasone, and asparaginase) reinduction or VXLD (vincristine, dexamethasone, pegylated asparaginase, and doxorubicin) or NECTAR (nelarabine, etoposide, and cyclophosphamide) regimen; targeted agents; or early-phase options. These could include a combination of up-front chemotherapy or standard salvage chemotherapy in addition to a targeted agent.

Historically, outcomes for patients with relapsed or refractory ALL have been poor. Relapse typically occurs within 2 years of diagnosis, with survival rates of less than 25%. Historical reinduction remission rates are approximately 30% to 40%, despite using intensive reinduction regimens. “Despite these promises and despite the kind of advances that we’ve made, getting to [allogeneic] stem cell transplant does remain a challenge, and outcomes remain dismal despite existing salvage regimens, even when including these targeted agents in early-phase trials,” Rouce said during the presentation.

Focus on immunotherapies, namely cell therapy, has been an exciting space in the past 5 to 6 years, and research has opened the door to using CAR T cells to target T-cell malignant tumors as opposed to limiting them to B-cell malignant tumors. When using CAR T cells to target a T-cell malignant tumor such as lymphoblastic leukemia and lymphoma, they can be designed to have antitumor activity against malignant cells that express the antigen.

However, experts must remain cognizant of the challenges associated with the development of CAR T-cell therapy for patients with T-cell malignant tumors. For example, CAR T cells can kill themselves, limiting expansion in the laboratory. This can limit their ability to kill tumor cells.

Previously, positive outcomes with CAR T cells targeting T-cell malignant tumors have been observed, including in autologous CAR T-cell trials where the cells are taken from the patient, genetically modified in the laboratory, expanded, and given back to the patient. In these trials, promising results regarding initial outcomes at day 28 were observed. In one trial (NCT04572308), 19 patients with a minimal residual disease (MRD)-negative result had a complete response (CR), and in another trial (NCT04004637), 7 of 8 patients had an overall CR.²

“This is exciting because most of these trials were initially designed to serve as a bridge before consolidative transplant. But a number of patients in these trials did not go on to transplant and still had prolonged complete responses, which is something that’s quite exciting. Also, looking at targeting using a CD7[-targeting] CAR T cell that’s either from a prior or future transplant donor or alternative donor…[has shown] promising outcomes in these patients, with about 50% of them going on [to] allo[geneic] transplant but still a number of patients being able to maintain remission without [it],” Rouce said.¹

MAGENTA Study

Looking at CD5-targeting CAR T cells in a phase 1 trial (NCT03081910), investigators assessed CD5 CAR T cells as a bridge to allogeneic hematopoietic stem cell transplant based on preclinical work, which showed that there would be limited in vivo persistence, which could translate to limited in vivo antitumor activity due to the risk of T-cell aplasia.³ Patients were required to have an available and willing transplant donor.

Pediatric and adult patients with mature T-cell lymphomas as well as patients with immature lymphoblastic lymphomas were treated.¹ Participants were heavily pretreated patients, with the majority having had at least 5 lines of prior therapy. Several patients had experienced relapse following allogeneic transplant and had primary refractory disease. The dose-escalation trial included 3 dose levels.

Eleven patients with T-ALL and 2 patients with T-cell lymphoblastic lymphoma (T-Lly) were treated. Reasons for nontreatment included progressive disease or comorbidity that led to ineligibility in the trial, leading experts to explore if an allogeneic transplant was a better option. This was due to 50% of referred patients having experienced relapse after a prior transplant and their prior transplant donor usually still being available, especially a sibling.

Findings from the study revealed promising responses, including in a patient with refractory peripheral T-cell lymphoma, which is a disease not typically seen in pediatric patients. This patient had avid disease based on positron emission tomography and had a CR 4 weeks after therapy.

Experts noticed early on that more responses were observed in patients with mature T-cell lymphoma, so they shortened the manufacturing period and added chemical inhibitors, which allowed for a less terminally differentiated CAR T-cell phenotype and enhanced the phenotype.

Since that time, there were more responses among patients with T-ALL, with two-thirds of patients treated since the manufacture change displaying a CR. However, this did not address the 41% of patients with T-ALL/ Lly who died prior to the ability to receive cells, even when manufacture was complete within 4 weeks.

Despite the shortened manufacture period and although CRs were observed in several patients with mature T-cell lymphoma, there was a lot of progressive disease.

A second arm of the study, arm B, was opened, where CD5 CAR T cells could be manufactured from a prior allogeneic transplant donor. So far, 3 patients with T-ALL who have experienced relapse multiple times have been enrolled. Two of the 3 patients have had MRD-negative CRs. Additionally, there are 2 pediatric patients who will be treated.

“But it also raises the question of if you have more antitumor activity, you may have more off-tumor, on-target effects. When targeting a T-cell antigen with a CAR that shares antigen on normal T cells, there are specific risks overall with our CD5 CAR T-cell study. We’ve had mild, manageable CRS [cytokine release syndrome], and we’ve seen some viral infections or reactivation related to T-cell aplasia. This is consistent across [findings for] all CAR T-cell studies for T-cell [malignant tumors], including the CD7 trials,” Rouce said.

Next Steps

Some proposed solutions to established risks when targeting T-cell antigens with a CAR include using a bridge to allogeneic transplant, performing frequent viral polymerase chain reaction monitoring, using rituximab to avoid the risk of Epstein-Barr virus (EBV)-related lymphoproliferative disease, and identifying off-the-shelf EBV T cells. New strategies are also being explored to eradicate CAR T cells, including the use of ruxolitinib.

Looking at alternative targets, especially for T-ALL and T-Lly, CD7 is present in 97% of patients. Because it is widely expressed, experts are working to target CD7 as well.

Off-the-shelf CAR T cells are also showing promise because they can eliminate manufacturing difficulties and delays and choose optimal donors with best preclinical activity.

Additionally, they are more fit and cost efficient. However, they can be a risk-ridden approach, so genetic manipulation to cells is needed to reduce the risk of graft-vs-hostdisease. These allogeneic cells may also be rejected in some situations, making manufacture strategies more complex, which can also create some regulatory hurdles.

“The harsh reality is that many patients [with] relapsed/refractory [disease] will require multiple modalities to achieve remission. We are fortunate that we have these agents, and we have early-phase trials that are incorporating small molecule and pathway inhibitors. Often, these patients may need multiple of these to…get to remission. CAR T-cell products are quite promising, but we do have manufacture challenges, especially in the autologous setting, and patient and disease-specific challenges, so we are moving more toward looking at offthe-shelf products.”

REFERENCES:

1. Rouce RH. Treatment of relapsed/refractory T-ALL including immunotherapy. Presented at: 2023 ASPHO Conference; May 10-13, 2023; Fort Worth, TX.

2. Zhang M, Chen D, Fu X, et al. Autologous nanobody-derived fratricide-resistant CD7-CAR T-cell therapy for patients with relapsed and refractory T-cell acute lymphoblastic leukemia/lymphoma. Clin Cancer Res. 2022;28(13):28302843. doi:10.1158/1078-0432.CCR-21-4097

3. Scherer LD, Brenner MK, Mamonkin M. Chimeric antigen receptors for T-cell malignancies. Front Oncol. 2019;9:126. doi:10.3389/fonc.2019.00126