Can a CAR T-Cell “Cocktail” Overcome Antigen Escape?

A sequential infusion of 2 third-generation chimeric antigen receptor (CAR) T cells targeting CD19 and CD22, respectively, was associated with a high response rate in patients with relapsed/refractory B-cell malignancies, according to findings from a small single-center study. These results, which were published in Blood by Na Wang, MD, from Huazhong University of Science and Technology in China, and colleagues, also suggest that this approach reduced antigen escape – a major cause of relapse.

“Anti-CD19 CAR T-cell therapy has yielded unprecedented efficacy in refractory/relapsed B-cell malignancies,” corresponding study author Liang Huang, MD, from Tongji Hospital in Wuhan, China, told ASH Clinical News. “However, CD19-negative relapse has emerged as a major challenge for long-term disease control after CAR T-cell therapy and confers a dismal outcome to these patients.”

In this pilot study, Dr. Huang and researchers evaluated this dual-targeting approach as a potential means of preventing antigen escape and subsequent relapse. A total of 89 patients with B-cell malignancies that had relapsed or were refractory to previous line of treatment, including allogenic or autologous hematopoietic cell transplantation, were enrolled:

  • 51 patients with B-cell acute lymphocytic leukemia (ALL)
  • 38 patients with B-cell non-Hodgkin lymphoma (NHL)

Participants’ median age was 36 years (range = 9-71). Most patients in the ALL cohort (71%) had high-risk cytogenetic and genomic aberrations. In the NHL cohort, “all patients manifested aggressive clinical courses,” with 61% having relapsed at least 3 times.

Per study protocol, patients received initial lymphodepletion chemotherapy (fludarabine 25 mg/m2 and cyclophosphamide 300 mg/m2 for a total of 3 days), then received separate infusions with CAR T-cell therapies targeting CD19 and CD22 on successive days.

Investigators assessed patient response via bone marrow aspiration every month for 6 months, then every 3 months thereafter. Patients were followed until they were lost to follow-up, withdrew consent, or had died. In addition, researchers monitored measurable residual disease (MRD) in blood, bone marrow, and cerebrospinal fluid using multiparameter flow cytometry.

Findings for the ALL Subgroup

In the subgroup of patients with ALL, doses of anti-CD19 and anti-CD22 CAR T cells were 2.6±1.5×106/kg and 2.76±1.2×106/kg, respectively.

At the 30-day assessment, 48 patients (96%) achieved an MRD-negative complete response (CR; defined as <0.01% bone marrow blasts) or CR with incomplete count recovery. This included all 12 patients who had received prior transplantation, the authors reported, and the overall response rate (ORR) was similar across all subgroups.

Of the patients who responded, half (n=24) later experienced a disease relapse, for a cumulative 12-month relapse incidence of 0.29. Notably, 23 of these patients relapsed with CD19/CD22–double-positive disease, indicating that only one patient experienced an antigen-loss relapse.

During a median follow-up of 16.2 months (range = 1.3-33.3), the median progression-free survival (PFS) in this group was 13.6 months (range = 6.5 to not reached [NR]), while the median overall survival (OS) was 31.0 months (range = 10.6-NR). The estimated 12-month PFS and OS rates were 53% and 63%, respectively.

The authors also observed that a lower leukemia burden (<5% bone marrow blasts) at baseline was associated with improved OS (p=0.008), whereas central nervous system involvement was associated with a reduced PFS (p=0.0003).

Findings for B-NHL Subgroup

In the NHL subgroup, patients received slightly higher doses of anti-CD19 and anti-CD22 CAR T cells: 5.1±2.1×106/kg and 5.3±2.4×106/kg, respectively.

With a minimum follow-up of 3 months, 26 patients responded to treatment, for an ORR of 72%. Half of these responses were CRs and 22% were partial responses (PRs). Most of the patients (n=15/18) who had a CR at 3 months maintained the response through a median follow-up of 15 months, the investigators reported.

Following CAR T-cell infusion, 6 patients subsequently underwent transplantation, all of whom maintained the initial CR without evidence of progressive disease. In this subgroup of patients, the best ORR, CR, and PR rates were as follows:

  • ORR: 83%
  • CR: 58%
  • PR: 25%

During a median follow-up of 14.4 months (range = 0.4-27.4 months) in the entire NHL subgroup, the median PFS and median OS were 9.9 months (range = 3.3-NR) and 18 months (range = 6.1-NR), while the estimated 12-month PFS and OS rates were 50% and 55%, respectively. Half of patients (n=18) experienced disease progression, with a median time to progression of 3.3 months (range = 1.0-14.8 months).

Looking at characteristics that could predict improvements in survival, the authors found that patients who were treated with the CAR T-cell cocktail at first relapse had longer survival, compared with those who received treatment for primary refractory disease or after multiple relapses. In addition, patients with NHL who maintained their response for at least 3 months had significantly greater PFS (p<0.0001) and OS (p<0.0001).

In the overall cohort, 85 of the 89 enrolled patients (96%) experienced cytokine release syndrome (CRS). The authors noted that 77% of these cases were classified as “low grade,” and all but one of the high-grade CRS cases were reversible.

The most commonly reported severe adverse events (AEs) were cytopenias, including lymphopenia (grade 4 in all 89 patients), neutropenia (grade ≥3 in all 89 patients), and leukopenia (grade ≥3 in 88 patients). A total of 3 patients experienced a fatal AE, one of whom died of grade 5 CRS and pneumonia, despite receiving tocilizumab, glucocorticoid, and plasma exchange. The other 2 patients died of infectious pneumonia.

Taken together, these efficacy and safety results suggest that “infusion of 2 single [antigen]-specific CAR T cells represents a feasible and reliable solution in clinical practice,” the authors concluded.

Despite the promise of combined CAR T-cell therapy in patients with B-cell malignancies, Dr. Huang noted potential limitations of this approach. “When compared with each single-specific CAR T cell, superior activity or improved survival was not demonstrated by [this investigational] cocktail but was seen in dual-specific CAR T cells in xenograft mice models,” said Dr. Huang. “Therefore, in addition to avoiding antigen loss relapse, efforts should be made to extend the lifespan of CAR T cells in vivo, if CAR T-cell therapy is intended to be a definitive therapy rather than a bridging therapy.”

Other limitations of this study include its small number of patients as well as its open-label, single-center, and noncontrolled design.

Study authors report relationships with Wuhan Bio-Raid Biotechnology Company, which manufactures CAR T-cell products.

References

Wang N, Hu X, Cao W, et al. Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies. Blood. 2020;135:17-27.

The idea of going after both targets at the same time, as explored in this study, seems to minimize or at the very least decrease the likelihood that treatment failure will be related to the loss of targeted antigen expression – at least at this early stage. It is easier for a tumor to delete one target, whereas it’s much harder for a tumor to delete both targets simultaneously. While this approach is not necessarily an incredibly novel idea, this is, to my knowledge, the first time it has actually been executed on a clinical level.

However, one could imagine that if this process ever gets commercialized, the costs of cell production would double, because there are two populations of cells instead of just the one. I also am somewhat skeptical about this approach in solid tumor malignancies, where there is much more heterogenous expression of target antigens. Whether this is an approach that’s viable in both solid and liquid tumors would remain to be seen.

Renier Brentjens, MD
Memorial Sloan Kettering Cancer Center
New York, NY