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The identification of immune responses required for durable control of childhood acute lymphoblastic leukemia

University of British Columbia

Remarkable clinical successes have been achieved with targeted immunotherapies directed at a surface antigen of leukemia blasts in patients with relapse or chemotherapy-refractory B-ALL. This single antigen-targeted approach, however, is highly prone to tumor immune escape. Development of resistance to therapy, commonly caused by the emergence of target-negative escape variants, remains a major drawback of CD19-directed therapies for B-ALL. The efficacy of strategies that direct T cell-mediated cytotoxicity towards leukemic cells bearing non-immunogenic antigens is limited, with a lack of evidence that these interventions establish immunological memory. In this study, I use the Eμ-ret mouse model to better understand the limitations of current single antigen-targeted immunotherapies and to identify immune responses required for the achievement and, more importantly, maintenance of remission in childhood B-ALL. My results uncovered the ability of target-directed therapy to elicit epitope spreading, enabling the generation of a secondary immune response against additional non-targeted leukemia-associated antigens that contributes to sustaining durable remission. Importantly, these results also suggest that such diversification of protective immune response is limited in an immunological setting where immune tolerance towards leukemia-associated antigens is established early in the course of leukemia progression. Furthermore, I have shown the ability of TLR agonist-mediated immune modulation to target leukemia cells in bone marrow, and induce durable immune control of primary B-ALL cells. Finally, I have demonstrated that NKT cells as a population is capable of influencing disease progression in the Eμ-ret mouse by playing a role in immunoediting. Overall, these findings support that the generation of immune response with a broad specificity for range of leukemia-associated antigens contributes to the maintenance of remission. Furthermore, my results suggest that overcoming immune tolerance established against leukemia-associated antigens may be critical for maximizing the therapeutic benefits of immunotherapies for childhood B-ALL. Collectively, the therapeutic impact of innate immune modulation presented here in the context of B-ALL may contribute to the eradication of MRD, and thus reduce the risk of relaspse in MRD-positive patients.

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2019-09-05

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71632

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/