A New Target for B-ALL CAR-T

In the past decade, immunotherapies targeting CD19 have revolutionized options for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). The CD19-targeting bispecific T-cell engager blinatumomab, and multiple chimeric antigen receptor T-cells (CAR-Ts) targeting CD19, including tisagenlecleucel and axicabtagene ciloleucel, have been demonstrated to be effective in pediatric patients with relapsed or refractory B-ALL.^1-3  Although these therapies are efficacious and induce long-term remissions in some patients, CD19-negative relapse remains a significant challenge in patients after CD19-targeted therapy. CD22 has been identified as an alternate target, and the CD22-targeted antibody-drug conjugate inotuzumab ozagamicin has been shown to be effective in patients with B-ALL.⁴  In a groundbreaking phase I trial, Dr. Nirali N. Shah and colleagues report the largest experience to date with a CAR-T targeting CD22.⁵ 

In this phase I trial, 58 participants were treated, with 57 patients evaluable. More than 80 percent of patients had received prior CD19-targeted therapy. Seventy percent of patients received a complete response, with 60 percent of patients achieving a minimal residual disease–negative response. Median overall survival was 13 months.

As with other CAR-Ts, the major toxicity associated with CAR-T22 is cytokine release syndrome (CRS), with more than three-fourths of patients in this study developing symptoms of CRS. The authors also describe a subset of patients who developed a recurrence of hypercytokinemia after resolution of initial CRS. The authors call this a hemophagocytic lymphohistiocytosis (HLH) -like phenomenon. This nomenclature is somewhat confounded as multiple groups have already established that CRS after CD19-targeting immunotherapies clinically, biologically, and pathophysiologically mirrors HLH.^6,7  Similar to HLH, CRS after CD19-directed immunotherapies has marked elevation of interferon gamma (IFN-γ), interleukin (IL) -10, and IL-6 along with hyperferritinemia and hypofibrinogenemia. Initial CRS after CAR-T22 also has a cytokine signature similar to HLH. The recrudescence of hypercytokinemia demonstrated high levels of IFN-γ, IL-6, and IL-10 but also had marked elevations of IL-1B and TNF-α, which are not typically highly elevated in CRS after CAR-T19 and may or may not be elevated in patients with HLH. Unlike IFN-γ, IL-6, and IL-10, which are universally elevated in HLH regardless of trigger, TNF-α and IL-1B are elevated in some patients with HLH yet normal in others. Marked elevations are more commonly seen in HLH because of rheumatologic diseases and inflammasomopathies.

As in previous studies, early CRS was treated with tocilizumab. The second wave of hypercytokinemia was successfully managed with anakinra. This bitemporal occurrence of CRS appears to be unique to CAR-T22 and additional studies into the biology of this phenomena are important. Bitemporal CRS was more pronounced in patients who received CD4/CD8 T-cell selection prior to infusion, implying that CD4/8 T-cells have a crucial role to play in the pathophysiology of hypercytokinemia in the setting of CAR-T22. Crucially, patients who received a lower dose of CD4/CD8 T-cell–selected CAR-T22 had preserved efficacy of treatment response, with an abrogation of CRS. This again demonstrates the link between development of CRS and efficacy of CAR-T that has been observed with CAR-T19.

Notably, three patients treated with CAR-T22 developed atypical hemolytic uremic syndrome (aHUS), a type of thrombotic microangiopathy, which required treatment with eculizumab. This has not been reported in patients receiving CAR-T19; however, it has also not been formally studied. Endothelial dysfunction, which characterizes thrombotic microangiopathy, has been invoked as a potential pathophysiologic mechanism in immune effector cell–associated neurotoxicity (ICANS). Rates of ICANS in patients treated with CAR-T22 were similar to rates with other CAR-T products, and perhaps less severe. This is an important area for future inquiry, especially with the increasing prevalence of new CAR-Ts against unique targets.

In this article, the authors make several key observations. First, they demonstrate the potential efficacy of a CAR-T against CD22, which can be used in patients who have had CD19-negative relapses following CD19-targeted immunotherapies. Second, they demonstrate that CAR-T22 has an inflammatory response distinct from that of CAR-T19, with development of a second wave of CRS, and with evidence of thrombotic microangiopathy in a subset of patients. This has critical implications for the development of CAR-Ts against other antigens and underscores the importance of studying the immune response that occurs to different CAR-Ts. Finally, the authors demonstrate the proof-of-concept that alteration in the manufacturing process to select a particular population of T-cells impacts both the efficacy of the product and the immune response.