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816 Evaluating the potential of harnessing anti-leukemia T cells for the treatment of T cell acute lymphoblastic leukemias (T-ALL)
  1. Todd Triplett1,
  2. Sarah Church2,
  3. Tyler Hether2,
  4. Joshua Rios3,
  5. Srividya Kottapalli4 and
  6. Nisha Holay4
  1. 1UT Dell Medical School, Austin, TX, USA
  2. 2NanoString, Seattle, WA, USA
  3. 3St. Edward’s University, Austin, TX, USA
  4. 4University of Texas at Austin, austin, TX, USA


Background T cell Acute Lymphoblastic Leukemia (T-ALL) is a devastating malignancy found primarily in pediatric populations. Standard of care for T-ALL has not progressed from intensive regimens of chemotherapy. Another therapeutic strategy for treating T-ALL is to harness anti-leukemia T cells by immunotherapy. Currently, whether T-ALL is sufficiently immunogenic to generate anti-leukemia T cells is unknown. Furthermore, it is unclear how differences in the immune milieu of distinct tissue types (lymphoid vs non-lymphoid) that become infiltrated by T-ALL impacts T cell interactions with leukemia.

Methods These studies utilized primary T-ALL cells from a murine model that were transplanted into immune-competent, congenic (CD45.1) recipient mice. Tissues were evaluated by flow cytometry at distinct stages of disease to help determine if T cells respond to T-ALL. In addition, frozen tissue sections were analyzed using NanoString’s GeoMX Digital Spatial Profiling platform to evaluate T cells in specific regions of varying proximity to T-ALL.

Results Drastic changes to the composition of the TME were found at distinct stages of tumor burden. Evaluation of changes to the hosts’ (CD45.1+) T cells revealed a higher frequency of CD8 T cells with an activated phenotype. Furthermore, this increase largely correlated with tumor burden (figure 1). As this may represent anti-leukemia T cell responses, we next determined if they could be harnessed with immunotherapies directed against T cell co-signaling receptors. Although PD1 and OX40 monotherapies had no discernable effect, the combination of anti-PD1 with anti-OX40 led to a drastic reduction in T-ALL burden. Importantly, control of tumor growth was accompanied by a concomitant increase in cytotoxic CD8 T cells actively undergoing proliferation specifically in response to combination therapy. To gain better insight into T cell interactions with T-ALL, frozen tissue sections were used for comprehensive digital spatial profiling using NanoString’s GeoMX platform. This analysis revealed strong correlations between immune markers indicative of anti-leukemia responses as well as suppressive factors. Interestingly, regions enriched for activation markers were largely constrained to certain regions indicating the formation of ‘immunological hotspots’ in the context of T-ALL.

Abstract 816 Figure 1

Increase in memory CD8+ T cells in response to T-ALLChanges to the T cell compartment were evaluated by transplanting primary T-ALL cells (CD45.2+) into immune-competent CD45.1 congenic recipient mice. T cells were then evaluated in the spleens at distinct stages of disease. As shown below, an increase in the frequency of CD8+ T cells that are memory (CD44+) and effector memory largely correlated with tumor burden in the spleens of transplanted mice that could indicate anti-leukemia T cell responses. Data is representative of a cohort from 1 of 3 independent experiments

Conclusions The results from these studies suggest that T-ALL is recognized by T cells. As immune responses were not uniform within an organ, it will be important to specifically evaluate these ‘immunological hotspots’ in order to identify targets to activate T cells found in these regions. Ongoing studies are therefore aimed at comparing T cell interactions with T-ALL and their responses to immunotherapy between tissue types.

Acknowledgements Analysis of tissue section was supported in part by a SITC-NanoString Technologies Spatial Profiling Award given to T.A.T.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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