From Aminopterin to Tisagenlecleucel: Childhood Acute Lymphoblastic Leukemia at the Forefront of Cancer Breakthroughs

Prior to the 1940s, acute lymphoblastic leukemia (ALL) was universally fatal. More than 50 years ago, Dr. Sidney Farber demonstrated that folate antagonist aminopterin could induce remission in children with ALL.¹  This seminal finding established that cytotoxic chemotherapy can kill cancer cells. Year by year, pioneers such as Drs. Gertrude Elion and George Hitchings, Emil Frei, Don Pinkel, and others, successively demonstrated improvement in care for these children, and today, approximately 90 percent of children diagnosed with ALL are cured.^2-4  ALL has been long been the vanguard for novel anti-neoplastic approaches.

Yet, even in pediatric ALL, not all children respond to treatment, and the short- and long-term adverse effects of therapy can affect health and quality of life significantly. Immunotherapies have the potential to improve outcomes with reduced adverse effects because of nonoverlapping toxicities with conventional cytotoxics, and 2018 saw gratifying developments in the application of these new agents.

The three main types of immunotherapies that have been used to treat ALL successfully are monoclonal antibodies (conjugated and unconjugated), bi-specific T-cell engagers (BiTEs), and chimeric antigen receptor engineered T cells (CAR-Ts) — arguably, the most groundbreaking immunotherapy to be studied in ALL.^5-9  As readers well know, CAR-T therapy involves genetic modification of T lymphocytes to express artificial receptors that can target surface antigens. CD19 is an ideal target for immunotherapy, especially with CAR-Ts. CD19 is found only on normal and malignant B cells and not on other tissues or organs, and is important for early-stage B-cell development, growth, and survival. The concept of using T cells to target malignancies was pioneered by Dr. Stephen Rosenberg and colleagues in the 1980s.¹⁰  Early trials using CAR-T were largely unsuccessful because of T cell anergy resulting in poor proliferation and persistence, due to a lack of co-stimulation. These first-generation CAR-Ts only contained a cytosolic domain and antibody-based external receptor. Second-generation CAR-Ts added T-cell co-stimulatory signaling domains such as 4-1BB or CD28, which have led to robust antitumor responses in preclinical models and patients.

Tisagenlecleucel (CTL019) is a CD19-targeting CAR-T developed in collaboration between the University of Pennsylvania (UPenn), Children’s Hospital of Philadelphia (CHOP), and Novartis Pharmaceuticals. This CTL019 product contained a CAR bearing the 4-1BB co-stimulatory domain, which was subsequently established to be highly effective in children with r/r B-ALL.^11,12  Similar observations were confirmed by others.^13-15  Tisagenlecleucel, the CAR-T product bearing the CTL019 construct, received FDA approval in 2017 and EMA approval in 2018 based on the results of the ELIANA trial.¹⁶  This study was a phase II, single-cohort international trial that treated more than 70 children and young adults with r/r B-ALL with a single infusion of tisagenlecleucel. In this refractory patient population, the overall remission rate at three months was 81 percent, and the 12-month EFS and OS were 50 percent and 76 percent, respectively. All patients who achieved CR were minimal residual disease (MRD) –negative. Integral to the success of tisagenlecleucel was the prolonged persistence of the CAR-Ts in the majority of patients. Results were updated at the 2018 ASH Annual Meeting, showing 66 percent of patients who had a CR remain in remission at 18 months.¹⁷  Tisagenlecleucel was the first gene therapy and first cellular therapy to be approved by the FDA or EMA, another historical breakthrough for childhood ALL.

T cell-engaging therapies including CAR-Ts and BiTEs have a unique toxicity profile. The two most serious and potentially life-threatening toxicities are cytokine release syndrome (CRS) and neurotoxicity. On the ELIANA trial, CRS and neurotoxicity occurred in 73 percent and 40 percent of patients, respectively. CRS is treated with the IL-6 inhibitor tocilizumab, which received FDA approval for this indication in 2017.¹⁶  Numerous recent studies have established that the biology of CRS is largely due to abnormal activation of macrophages, leading to a clinical picture that mirrors hemophagocytic lymphohistiocytosis with abnormal elevation of multiple cytokines including IFN-α, IL-6, and IL-10.^18,19  The biology and management of neurotoxicity seen after CAR-T therapy is less understood; however, recent work suggests it may be mediated by abnormal endothelial activation with breakdown of the blood brain barrier, hypercytokinemia, disruption of the ANG-TIE2 axis, and elevated endogenous excitatory neurotransmitters.^20-22  Finally, recent preclinical work suggests neurotoxicity may be ameliorated by IL-1 blockade.^23,24 

Key considerations for the immediate future of CAR-Ts for ALL include: 1) determining if CAR-Ts should be considered definitive therapy or used as a bridge to hematopoietic stem cell transplantation; 2) testing whether they can be used to replace cytotoxic therapy and move into the frontline setting; 3) elucidating mechanisms of relapse and resistance, including antigen-escape and loss of T-cell persistence, and investigating methods to overcome these problems, such as CAR-Ts that target multiple surface antigens or combining CAR-Ts with checkpoint blockade; 4) further development of allogeneic “off-the-shelf” products that reduce the one- to two-month lag time between collection of T cells and infusion of a product and that circumvent poor autologous T-cell numbers or function; and 5) translating CAR Ts that can be used to treat T-ALL. At the 2018 ASH Annual Meeting, dozens of abstracts from multiple groups presented new data addressing all of these questions.

In summary, from the first use of cytotoxic chemotherapy to the first FDA approval of a gene therapy, childhood ALL has been at the forefront of new treatment breakthroughs for 80 years.