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Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia

Leukemia volume 32, pages 539–542 (2018)Cite this article

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A Corrigendum to this article was published on 05 January 2018

This article has been updated

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While most children are cured, outcomes among very high-risk or relapsed patients remain poor. Strategies to direct T-cell-mediated cytotoxicity towards leukemic cells bearing non-immunogenic antigens, such as CD19-targeted chimeric antigen receptor-modified T cells (CAR-T)1 and bi-specific T-cell engagers,2 have tremendous clinical promise for ALL, achieving complete remissions in the majority of patients in early trials. Unfortunately, there is no evidence that these interventions generate long-term immune memory, and relapses of target antigen-positive clones may emerge after engineered receptors are no longer present.1 Furthermore, antigen-negative relapses show that immunoediting may render single antigen targeting insufficient to prevent escape.3 To understand these treatment failures better and to identify the T-cell activities necessary for durable protection against ALL recurrence, we evaluated neoantigen-driven remission in the Eμ-ret mouse model of B-cell precursor ALL.

In contrast to the adoptive transfer setting, the first exposure of the immune system in children with ALL to leukemia-associated antigens does not occur just prior to diagnosis but rather during fetal development, as most children with ALL have pre-leukemic cells detectable at birth.9 The initiating genetic event and presentation of resulting neoepitopes, therefore, occur during a time of extensive immune tolerance induction. Leukemia in Eμ-ret mice similarly develops after additional genetic changes within an abnormal B-cell precursor population that arises in utero. To evaluate how tolerance to antigens associated with early-occurring initiating events affects the generation of protective responses through epitope spreading, we challenged healthy Eμ-ret mice with GFP/luc-modified ALL. Unlike GFP/luc-transgenic mice who succumb to GFP/luc-modified ALL as quickly as to unmodified ALL (Figure 1c), Eμ-ret mice are able to respond to the GFP/luc antigens and achieve a remission state with similar kinetics to wt BALB/c mice naïve to transgene-associated antigens (Figure 2d). However, while this response results in the prolonged survival of Eμ-ret recipients of GFP/luc-modified ALL, they all eventually succumb to disease in contrast to transgene-associated antigen-naïve wt BALB/c mice (Figure 2e). Epitope spreading-dependent durable protection was also observed when an endogenous protein, CD1d, was the target for the primary immune response (Supplementary Figure S1), showing a diversified T-cell response against tumor-associated antigens can be induced by syngeneic proteins and is not limited to a xenogeneic antigen-driven response.

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Change history

  • 05 January 2018

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue

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Acknowledgements

We thank Jennie Altman, Arnawaz Bashir and Hamid Bassiri, MD, PhD, for technical assistance and manuscript review. This research was supported by a St. Baldrick’s Scholar Award (DMB); a grant from the Pennsylvania Department of Health (SAG); operating grants from Canadian Institutes of Health Research (MOP-126122) and the Leukemia & Lymphoma Society of Canada (GSDR); and an American Cancer Society Mentored Research Scientist Grant in Applied and Clinical Research (MRSG-12-215-01-LIB), a Hyundai Hope on Wheels Scholar Award, and the Richard and Sheila Sanford Endowed Chair in Pediatric Oncology, Children’s Hospital of Philadelphia (AES).

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  1. G S D Reid and A E Seif: These authors contributed equally to this work.

Authors and Affiliations

  1. Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada

    S Jo & G S D Reid

  2. Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    J H Lee, J J Mattei, D M Barrett, S A Grupp & A E Seif

  3. Department of Pediatrics, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA

    J H Lee, J J Mattei, D M Barrett, S A Grupp & A E Seif

  4. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

    P van den Elzen & G S D Reid

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Correspondence to A E Seif.

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Jo, S., Lee, J., Mattei, J. et al. Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia. Leukemia 32, 539–542 (2018). https://doi.org/10.1038/leu.2017.290

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