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P06.07 CXCR6 expression enhances accumulation of anti-mesothelin CAR T cells at the tumor site and their therapeutic efficacy in pancreatic cancer xenografts
  1. S Stoiber1,
  2. S Lesch1,
  3. J Ogonek1,
  4. B Cadilha1,
  5. M Benmebarek1,
  6. A Gottschlich1,
  7. P Metzger1,
  8. C Hörth1,
  9. A Nottebrock1,
  10. S Endres1,2 and
  11. S Kobold1,2
  1. 1Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Member of the German Center for Lung Research, Munich, Germany
  2. 2German Center for Translational Cancer Research (DKTK), Munich, Germany


Background Chimeric antigen receptor (CAR) T cell therapy is currently approved for the treatment of some hematological malignancies. However, CAR T cells have so far lacked efficacy in the treatment of solid tumors. A major hurdle of CAR T cell therapy is the limited infiltration of CAR T cells into tumor tissue. Chemokine receptors enable immune cells to migrate along a chemokine gradient. Here, we show that overexpression of the C-X-C chemokine receptor 6 (CXCR6) enhances CAR T cell accumulation in C-X-C motif ligand 16 (CXCL16)-positive xenograft pancreatic cancer models, resulting in increased anti-tumor potency of anti-mesothelin CAR T cells.

Materials and Methods Human T cells were retrovirally transduced with an anti-mesothelin CAR and CXCR6. NSG mice were injected subcutaneously with mesothelin-CXCL16-overexpressing tumor cells. Mice were treated once with CAR-, CAR-CXCR6- or mock-transduced T cells when tumors were palpable and tumor size was monitored with a caliper. In a separate tracking experiment, subcutaneous tumors were established as described above and the presence of T cells at the tumor site was determined by FACS analysis within one week after adoptive T cell transfer. For orthotopic xenograft experiments mesothelin-CXCL16-overexpressing tumor cells were directly injected into the pancreas of NSG mice and one-time treatment with CAR-, CAR-CXCR6- or mock T cells was performed 5 days post tumor injection.

Results In a subcutaneous xenograft model of pancreatic cancer CXCR6-expressing CAR T cells displayed improved anti-tumoral potency compared to CAR T cells without CXCR6, resulting in prolonged survival of mice and tumor clearance in 9 out of 10 CAR-CXCR6-treated mice. A tracking experiment confirmed the increased accumulation of CAR-CXCR6 T cells compared to CAR T cells at the subcutaneous tumor site, suggesting increased migratory capacity of CAR-CXCR6-transduced T cells towards CXCL16-expressing tumors as the mode of action. Treatment of orthotopic pancreatic cancer xenografts similarly revealed prolonged survival of CAR-CXCR6-treated animals in comparison to CAR-treated animals, suggesting improved anti-tumor efficacy of CAR-CXCR6-transduced T cells.

Conclusions Forced expression of CXCR6 in anti-mesothelin CAR T cells increased the accumulation of CAR T cells at the CXCL16-positive tumor site, resulting in improved survival of treated mice and in complete tumor rejection in the majority of cases. This data reveals the potential of CXCR6 to direct CAR T cells to the tumor site and this approach may therefore be an attractive strategy to target a major pitfall in the translation of CAR T cell therapy to solid tumors.

Disclosure Information S. Stoiber: None. S. Lesch: None. J. Ogonek: None. B. Cadilha: None. M. Benmebarek: None. A. Gottschlich: None. P. Metzger: None. C. Hörth: None. A. Nottebrock: None. S. Endres: None. S. Kobold: None.

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