Ciltacabtagene autoleucel
Ciltacabtagene autoleucel, a 4-1BB–based CAR T-cell therapy with two BCMA-targeting domains, confers high-avidity binding. In the phase 1b/2 CARTITUDE-1 study, conducted in the United States and Europe, preliminary results in 97 patients showed a 97% response rate with ciltacabtagene autoleucel (target dose 0.75 × 106 CAR T cells per kg), and in 65 patients, a complete response (67%). Progression-free survival at 12 months was 77% (95% CI, 66-84) and overall survival was 89% (95% CI, 80-94).3
Evan Oto/Science Source
Multiple myeloma can lead to bone lesions, osteoporosis, pathological bone fractures, and hypercalcemia.
In the phase 1 LEGEND-2 study4 that was conducted at four sites in China among less heavily pretreated multiple myeloma patients, while all used the same CAR construct, sites used variable conditioning regimens (split versus single). In the site using cyclophosphamide as the lymphodepletion therapy and three split CAR T-cell infusions, partial response or better was achieved in 50 patients (88%) with a median of three prior therapy lines. The complete response rate was high (74%) and minimal residual disease negativity was reached in 39 patients (68%). Median progression-free survival was 19.9 months (95% CI, 9.6-31.0), but 28.2 months among those with complete responses (95% CI, 19.9-not estimable). Median overall survival was also favorable at 36.1 months (95% CI, 26.4-not estimable); it was 35.0 months-not estimable among patients with complete responses. Results from the other three sites were comparable.
Noteworthy among other BCMA-targeting CAR T-cell products in earlier stages of clinical development is orvacabtagene autoleucel, which has a fully human BCMA-specific binding domain. At higher doses (300 × 106 to 600 × 106 CAR T cells) among 62 patients with triple-class–exposed multiple myeloma in the EVOLVE trial, 92% had a partial or better response, with complete responses or better in 36%, all with an encouraging safety profile.
BCMA-targeting CAR T cell toxicity
While van de Donk, Usmani, and Yong, in their review1 note a lack of evidence of off-target toxicity with BCMA-targeting CAR T-cell therapy in clinical studies so far, they do point to several clinical syndromes (cytokine release syndrome, infections, respiratory failure, neurotoxicity, pulmonary aspergillosis, gastrointestinal hemorrhage) caused by cytokines produced during CAR T-cell expansion and to cytopenias and infections arising from prior treatment, bridging therapy, and lymphodepleting conditioning. Deaths attributed to treatment in the above-mentioned trials underscore the need for careful monitoring and early intervention.
Cytokine release syndrome
In the BCMA-targeting CAR T-cell therapy studies, the frequency of cytokine release syndrome varies widely from 17% to 95% but is generally attributed to CAR T-cell activation and is associated with increased serum ferritin concentrations, high c-reactive proteins, and proinflammatory cytokines. High tumor load, in multiple myeloma patients receiving CD19-targeting CAR T cells, was associated with a higher incidence of severe cytokine release syndrome. In a small number of patients, macrophage activation syndrome and hemophagocytic lymphohistiocytosis, the most aggressive variants of cytokine release syndrome, are caused by severe immune activation and lead to multiorgan dysfunction.
Neurotoxicity
Immune effector cell–-associated neurotoxicity syndrome (ICANS) symptoms, in multiple myeloma patients treated with BCMA-targeting CAR T cells, may include delirium, transient confusion, aphasia, lethargy, tremor, dysgraphia, seizures, cerebral edema, and rarely, posterior reversible encephalopathy syndrome.1 While the pathophysiology of CAR T cell–related neurotoxicity is not well understood, high tumor load, higher peak concentrations of CAR T cells, and more severe cytokine release syndrome are more common in patients with severe neurotoxicity. “The frequency of neurotoxicities,” Dr. Yong noted in an interview, “has been reduced by steps taken to mitigate these risk factors.”