Jeffery White

Introduction: B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in children.^1,2 B-ALL arises when the highly regulated process of differentiation of hematopoietic stem cells to mature B cells goes awry.^1,3 Managed by multiple tightly regulated processes, it is difficult for a faulty B cell to escape termination. However, in the case of B-ALL, malignant B lymphoid cells inhibit differentiation, resulting in the uncontrollable proliferation and survival of faulty B cells that spread throughout the body.^1-3 Currently, the standard treatment of B-ALL involves chemotherapy administered in multiple sessions over the course of 2-3 years. The current 5 year survival rate is under 70% and relapse remains a serious issue with very poor outcomes.¹ To overcome this, new strategies to treat  B-ALL must be explored further. The next generation of immunotherapies may hold solutions to the poor prognosis of relapsed B-ALL.  Methods: While traditional CD19 targeted immunotherapy has shown much better survival rates it too comes with its shortcomings.^4,5 Some patients will show resistance to traditional immunotherapy which was associated with relapsed B-ALL and very poor outcomes.^5-7 New immunotherapies have been developed to avoid these shortcomings. CD22-targeted CAR T cells aim to treat resistance to traditional CD19 directed T cells by creating an immunotherapy that targets CD22.⁶ Additionally, anti-CD19 scFv humanized CAR-T immunotherapy was created to give immunotherapies increased persistence in the bone marrow and peripheral blood. Anti-CD19 scFv hCAR-T immunotherapy was infused into patients with relapsed ALL and the patients’ peripheral blood was evaluated.⁷  Results: In one phase I trial, 21 patients were selected to receive a novel CD22-CAR T cell therapy. 17 of these patients had previously received a CD19 directed immunotherapy and had entered relapse.⁶ Complete remission was achieved in 90% of patients that had received prior traditional CD19 directed immunotherapy, including 5/5 who enrolled with CD19dim/neg B-ALL.⁶ In the second experiment, anti-CD19 scFv hCAR-T therapy resulted in sustained therapeutic efficacy, with every patient in the trial entering complete remission. Six of which were in CR for over 18 months without further treatment.⁷  Conclusion: These experiments proved that next generation immunotherapies offer much higher remission rates and improve survival rates significantly more than the standard treatments used today.^{1, 5-7} CD22 directed immunotherapy confirmed another modality to diminish the poor outcomes of relapsed/refractory B-ALL when traditional treatments fail.⁶ Anti-CD19 scFv hCAR-T therapy resulted in sustained therapeutic efficacy in treatment of relapsed/refractory B-ALL and long term persistence of CAR T cells compared to traditional CD19 immunotherapies.⁷

1. Huang FL, Liao EC, Li CL, Yen CY, Yu SJ. Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: Molecular pathways and disease treatments. Oncol Lett. 2020;20(1):448-454. doi:10.3892/ol.2020.11583
2. Fitch B, Roy R, Geng H, et al. Human pediatric B-cell acute lymphoblastic leukemias can be classified as B-1 or B-2-like based on a minimal transcriptional signature. Exp Hematol. 2020;90:65-71.e1. doi:10.1016/j.exphem.2020.09.184
3. Jha KK, Dutta HS. Mutual Information based hybrid model and deep learning for Acute Lymphocytic Leukemia detection in single cell blood smear images. Comput Methods Programs Biomed. 2019;179:104987. doi:10.1016/j.cmpb.2019.104987
4. Mueller KT, Waldron E, Grupp SA, et al. Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. Clin Cancer Res. 2018;24(24):6175-6184. doi:10.1158/1078-0432.CCR-18-0758
5. Park JH, Rivière I, Gonen M, et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):449-459. doi:10.1056/NEJMoa1709919
6. Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20-28. doi:10.1038/nm.4441
7. Heng G, Jia J, Li S, et al. Sustained Therapeutic Efficacy of Humanized Anti-CD19 Chimeric Antigen Receptor T Cells in Relapsed/Refractory Acute Lymphoblastic Leukemia. Clin Cancer Res. 2020;26(7):1606-1615. doi:10.1158/1078-0432.CCR-19-1339