CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial

Abstract

PURPOSE Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells. PATIENTS AND METHODS We conducted a single-center, phase I, 3 + 3 dose-escalation trial with a large expansion cohort that tested CD22-targeted CAR T cells for children and young adults with relapsed/refractory CD22+ malignancies. Primary objectives were to assess the safety, toxicity, and feasibility. Secondary objectives included efficacy, CD22 CAR T-cell persistence, and cytokine profiling. RESULTS Fifty-eight participants were infused; 51 (87.9%) after prior CD19-targeted therapy. Cytokine release syndrome occurred in 50 participants (86.2%) and was grade 1-2 in 45 (90%). Symptoms of neurotoxicity were minimal and transient. Hemophagocytic lymphohistiocytosis–like manifestations were seen in 19/58 (32.8%) of subjects, prompting utilization of anakinra. CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility as well as heightened inflammatory toxicities, leading to dose de-escalation. The complete remission rate was 70%. The median overall survival was 13.4 months (95% CI, 7.7 to 20.3 months). Among those who achieved a complete response, the median relapse-free survival was 6.0 months (95% CI, 4.1 to 6.5 months). Thirteen participants proceeded to stem-cell transplantation. CONCLUSION In the largest experience of CD22 CAR T-cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy.

Efficient elimination of primary B-ALL cells in vitro and in vivo using a novel 4-1BB-based CAR targeting a membrane-distal CD22 epitope

“…Our hCD22.7-derived membrane distal-targeting CAR has not been functionally compared side-by-side with other membrane proximal-targeting CD22-scFvs used already in clinical trials, 15 21 with which Fry et al published discrete complete remission (CR) rates of 57% with a median remission duration of 6 moths in patients with R/R B-ALL treated with m971-CD22-CAR T cells 15 and in a more recent study they reported CR of 70% with a median relapse-free survival of 6 months. 23 However, the hCD22.7-CAR performs efficiently in vitro and in vivo using clinically relevant patient samples of B-ALL with different aggressiveness. This coupled to the long-term persistence of hCD22.7-CAR T cells, the lack of antigenic loss in vivo in the few CAR-resistant B-ALL cells, its high affinity, and its immunogenicity similar to m971 and HA22 CD22-scFvs provides support for its clinical validation as either single or tandem CD22–CD19-CAR for both naive and anti-CD19-resistant patients with B-ALL.…”

Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation

“…CRS can manifest clinically on a spectrum of acuity ranging from constitutional symptoms of fever, fatigue, headache, and myalgia to severe end-organ toxicity, hemodynamic shock, respiratory failure, and death [67,68,70]. In rare cases, CAR T cell therapy has been linked to the induction of an rHLH/MAS-like syndrome, which may be a progression to the most severe end of the CRS spectrum [75,76]. Common features of CRS as well as HLH and MAS are shown in Table 1.…”

Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients

“…A prolonged life-threatening systemic inflammatory response resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) (10) has been increasingly recognized as one part of the spectra of toxicities occurring after anti-CD19 CAR T cell infusion or CD19-directed blinatumomab, a bispecific T cell engager therapy (14). HLH-like manifestations have also been seen after anti-CD22 CAR T cell therapy (16). HLH and MAS are clinical syndromes of pathologic hyperinflammation and uncontrolled macrophage activation associated with triggers such as viral infections and rheumatologic diseases (17,18).…”

“…HLH and MAS are clinical syndromes of pathologic hyperinflammation and uncontrolled macrophage activation associated with triggers such as viral infections and rheumatologic diseases (17,18). Similarly, patients with CAR T cell-associated HLH-like toxicities present with prolonged cytopenia, hemophagocytosis, hyperferritinemia, fever, coagulopathy, liver function abnormalities, splenomegaly, and other organ dysfunction (14,16).…”