Despite a number of barriers and complications for autologous agents, there are a total 44 CAR-T* therapies in the pipeline for chronic lymphocytic leukemia (CLL), says GlobalData.

Autologous CAR-T therapy is a patient-specific immunotherapy that involves the genetic modification of a patient’s own T cells to attack their cancer. However, this therapy is typically less effective for CLL patients, as their T-cells are often dysfunctional and are not viable for this procedure.

Longest chronic lymphocytic leukemia remission achieved through CAR-T

In 2010, two patients with end-stage refractory CLL were administered Novartis’ anti-CD19 CAR-T therapy Kymriah (tisagenlecleucel) as part of a Phase I trial. In March 2022, it was reported that these two patients were still in remission, making this the longest-known CLL remission after CAR-T therapy, and demonstrating to the industry that long-term remission is indeed possible. However, there are still no approved CAR-T therapies for CLL.

Sam Warburton, Oncology Analyst at GlobalData, comments: “Patients with end-stage CLL have yet to benefit from an approved cell therapy, despite many developers initially trialing autologous CAR-T agents such as Kymriah and Yescarta in CLL during Phase I studies. The sales potential for entering a durable and effective therapy into the third-line refractory setting is enormous, considering the sizeable patient numbers and high unmet need for these patient populations, but there are several barriers that will impede the clinical progression of CAR-T agents in CLL.”

CAR-T therapy for non-Hodgkin’s lymphoma and acute lymphocytic leukemia

Many other B-cell malignancies such as non-Hodgkin lymphoma (NHL) and acute lymphocytic leukemia (ALL) have benefited profusely from the approvals of Gilead’s autologous anti-CD19 CAR-T therapy Yescarta (axicabtagene ciloleucel) and Kymriah.

Warburton continues: “Autologous CAR-T agents are now becoming the standard of care for NHL and ALL patients in the third line and later settings, providing lucrative returns for these agents. Such positive results mean that such indications are prioritized over CLL patients, who continue to miss out on these benefits.”

Effective standard treatments for CLL reduce it as a CAR-T priority

However, despite the demonstration of long-term remission, there are also clinical challenges to overcome before a CAR-T therapy for CLL can be fully realized.

Warburton continues: “Autologous CAR-T therapy does not easily lend itself to treating CLL, and the current standards of care in CLL such as AbbVie’s/Johnson & Johnson’s Imbruvica (ibrutinib) and Biogen’s/Roche’s Rituxan (rituximab) are well-established, well-tolerated, and effective options that can elicit long-term disease control that can last for over a decade. Cell therapies are, therefore, likely to be relegated to refractory patients with end-stage disease that are blocked from entering the more lucrative early lines of therapy.”

Allogeneic therapies may be best placed to meet unmet needs

Notwithstanding these challenges, CAR-T remains an area of intense research and development in the CLL pipeline. According to GlobalData’s Pharma: Pipeline & Marketed Drugs Database 38 of the of the 44 agents in development are autologous CAR-T agents while 11 are “off-the-shelf” allogeneic therapies which contain T-cells taken from another patient. Of the total, 37 agents are in clinical trials, with the remaining in either preclinical or discovery phases.

Warburton adds: “Allogeneic therapies may be more conducive to meeting unmet needs in CLL, considering the manufacturing complications for autologous agents. However, allogeneic CAR-T therapies are associated with unacceptable safety profiles, including reports of life-threatening graft vs host disease (GvHD) and cytokine release syndrome that would not be tolerable for unfit CLL patients.

“The low safety profile of allogeneic therapies may leave an opportunity for CAR-natural killer (CAR-NK) therapies**, which show promise for reduced risk of GvHD but are currently facing issues regarding inefficient in vitro expansion and suboptimal in vivo persistence —resulting in a relatively small CAR-NK pipeline in CLL, with only six agents in development.”

* Anti-CD19 chimeric antigen receptor T-cell

** Chimeric antigen receptor natural killer cell