Terry J. Fry, MD
While clinical trial findings with chimeric antigen receptor (CAR) T-cell therapy have impacted the landscape of pediatric acute lymphoblastic leukemia (ALL), most notably with the 2017 FDA approval of tisagenlecleucel (Kymriah), additional CAR T-cell products continue to be investigated.
"The behavior of CAR T cells can be different based on certain details, and that behavior can probably be incorporated into the likelihood of durability, and perhaps cure," said Terry J. Fry, co-director of the Human Immunology and Immunotherapy Initiative at the University of Colorado Anschutz Medical Campus. "I am not saying that any of these constructs are better than another...I just think that details do matter and are worth discussion."
So far, the CAR T-cell therapy that has been extensively studied and approved for pediatric patients with ALL is tisagenlecleucel, explained Fry in a presentation during the 2018 SOHO Annual Meeting. In August 2017, the FDA approved the anti-CD19 CAR T-cell therapy tisagenlecleucel for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.
Findings from a single-center phase I/II study of tisagenlecleucel were recently published in the New England Journal of Medicine
. In this global experience, investigators noted that tisagenlecleucel induced durable remissions after a single infusion in pediatric and young adult patients with relapsed/refractory B-cell ALL. Remissions were long-lasting and persistent, and caused only transient high-grade toxic effects.
Of the 75 patients that received an infusion, the overall remission rate in the first 3 months was 81%. At 6 months, the event-free survival rate was 73% (95% CI, 60%-82%) and the overall survival rate was 90% (95% CI, 81%-95%). At 12 months, rates were 50% (95% CI, 35%-64%) and 76% (95% CI, 63%-86%), respectively. At the time of the February 2018 publication, the median duration of response had not yet been reached. Notably, tisagenlecleucel was observed in the blood for up to 20 months.
The general themes of successful CAR T-cell therapy for patients with ALL, according to Fry, are lack of primary toxicity, meaning the occurrence of cytokine release syndrome—the severity of which is correlated with disease burden. The cell dose required for treatment is remarkably small, as it requires a capacity for exponential expansion, Fry explained. The durability of response in ALL likely requires CAR T-cell persistence. Additionally, antigen loss will occur as a cause of relapse, and retreatment often fails, he noted.
Fry explained that the convergence of acquired mutations and alternative splicing of CD19 enables resistance to anti-CD19 CAR T-cell therapy. Additionally, some patients will relapse after a CD22 CAR T-cell therapy, which Fry said is associated with reduced antigen surface expression.
In the clinic, investigators are targeting multispecific CD19/22 CAR T cells for treating patients with B-cell ALL in multiple trials:
NCT03330691 is a feasibility and safety study of dual CD19 and CD22 CAR-T cell therapy for patients with CD19- and CD22-positive leukemia and lymphoma using co-administration with 1 and 2 vectors. NCT03241940 is evaluating a CD19/CD22 CAR T cell product with chemotherapy in children and young adults with recurrent or refractory CD19-positive B-ALL. NCT03233854 mirrors NCT03241940, but includes patients with recurrent or refractory CD19-positive diffuse large B-cell lymphoma. NCT03448393 is investigating a CD19/CD22 CAR T-cell therapy in children and young adult patients with recurrent or refractory CD19/CD22-expressing B cell malignancies.
NCT03241940, NCT03233854, and NCT03448393 are all using TanCAR, a bivalent receptor.
There are several clinical efforts currently aiming to improve CD22- and CD19-directed CAR T-cell therapy remission durability. Poor T-cell expansion can contribute to a lack of CAR persistence, leading to the failure of the treatment, Fry said. Ways to combat this are the addition of checkpoint inhibitors and vaccines, which are both being investigated. For leukemia resistance, Fry suggested multispecific targeting, target antigen modulation, and alternative targets.
Maude SL, Laetsch TW, Jochen Buechner J, et al. Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med. 2018; 378:439-448. doi: 10.1056/NEJMoa1709866.