High risk, high reward – the future of CAR-T therapy in CLL

In 2010, two patients with end-stage refractory chronic lymphocytic leukaemia (CLL) were administered Novartis’ autologous anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy, Kymriah (tisagenlecleucel), as part of a Phase I trial. In March this year, 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 currently no approved CAR-T therapies for CLL, despite the fact that many other B-cell malignancies such as non-Hodgkin’s lymphoma (NHL) and acute lymphocytic leukaemia (ALL) have benefited profusely from the approvals of Gilead’s autologous anti-CD19 CAR-T therapy Yescarta (axicabtagene ciloleucel) and Kymriah. 

Autologous CAR-T agents are now becoming the standard of care for patients in the third line and later settings, providing lucrative returns for these agents. According to GlobalData’s analyst consensus forecast, Yescarta is expected to reach peak sales of $1.8bn in 2028, and Kymriah is expected to reach sales of $686m in the same year. 

Patients with end-stage CLL have yet to benefit from an approved cell therapy, despite many developers initially trialling autologous CAR-T agents such as Yescarta and Kymriah in CLL during Phase I studies. The sales potential for entering a durable and effective therapy into the third-line refractory setting is high, considering the sizeable patient numbers and high unmet need for these patient populations. However, several barriers will impede the clinical progression of CAR-T agents in CLL and result in other indications that are more amenable to CAR-T therapy being prioritised, such as NHL and ALL, both of which have demonstrated far superior overall response rates to CAR-T therapy compared with CLL. 

Although CLL is a B-cell malignancy, patients also suffer from dysfunctional T-cells that exhibit an exhausted phenotype. Autologous CAR-T therapy does not easily lend itself to treating CLL, as it relies on extracting functional T-cells from the patient’s blood and genetically modifying them in vitro. Additionally, chemotherapy regimens employed in treating CLL are known to deplete viable T-cell numbers, further exacerbating the lack of functional T-cells available to generate CAR-T cells. 

From a clinical perspective, CAR-T therapy may not be appropriate for patients who are typically eligible for cell therapies. Usually, patients who are refractory to standard of care and have been treated with at least two or more lines of therapy. In CLL, these patient populations are often very unfit and exhibit a high degree of comorbidities, making them less able to tolerate CAR-T therapy-associated toxicity and raising the bar for what qualifies as a tolerable safety profile. Conversely, the current standards of care, 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 lasts for decades. 

Cell therapies are, therefore, likely to be relegated to refractory patients with end-stage disease and are blocked from entering the more lucrative, early lines of therapy. This stands in contrast to other B-cell malignancies, such as NHL, where CAR-T agents are approved in third-line and later settings, but are targeting label expansions into earlier lines of therapy by virtue of being able to compete with the current standards of care in these settings, making these indications much more attractive targets. 

Despite these barriers, significant potential remains for cell therapies to penetrate the CLL market due to the high unmet need for end-stage refractory patients who require more durable and effective treatment options. The CLL pipeline is rich in CAR-T therapies, with 38 autologous and 11 allogeneic CAR-T agents currently in development, 37 of which are in clinical trials with the remaining agents in preclinical/discovery phases, according to GlobalData's Pharma Intelligence Centre. 

Allogeneic therapies may be more conducive to meeting unmet needs in CLL considering the manufacturing complications for autologous agents, although allogeneic CAR-T therapies are associated with unacceptable safety profiles. These include reports of life-threatening graft versus host disease (GvHD) and cytokine release syndrome, which would not be tolerable for unfit CLL patients. This 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.