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746 Vectorized Treg-depleting anti-CTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject “cold” tumors
  1. Monika Semmrich1,
  2. Jean-Baptiste Marchand2,
  3. Matilda Rehn1,
  4. Laetitia Fend2,
  5. Christelle Remy-Ziller2,
  6. Petra Holmkvist1,
  7. Nathalie Silvestre2,
  8. Carolin Svensson1,
  9. Patricia Kleinpeter2,
  10. Jules Deforges2,
  11. Fred Junghus1,
  12. Linda Martensson1,
  13. Johann Foloppe2,
  14. Ingrid Teige1,
  15. Eric Quemeneur2 and
  16. Bjorn Frendeus1
  1. 1BioInvent International AB, Lund, Sweden
  2. 2Transgene SA, Illkirch-Grafenstaden, France


Background Immune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, a majority of cancer patients including those with poorly immune infiltrated “cold” tumors are resistant to currently available ICB therapies. CTLA-4 is one of few clinically validated targets for ICB, but toxicities linked to efficacy in approved anti-CTLA-4 regimens have restricted their use and precluded full therapeutic dosing. At a mechanistic level, accumulating preclinical and clinical data indicate dual mechanisms for anti-CTLA-4; immune checkpoint blockade and Treg depletion are both thought to contribute efficacy and toxicity in available, systemic, anti-CTLA-4 regimens. Accordingly, strategies to deliver highly effective, yet safe, anti-CTLA-4 therapies have been lacking. Here, BioInvent and Transgene present and preclinically characterize a highly efficacious and potentially safe strategy to target CTLA-4 in the context of oncolytic virotherapy.

Methods A novel human IgG1 CTLA-4 antibody (4-E03) was identified using function-first screening for mAbs and targets associated with superior Treg depleting activity. A tumor-selective oncolytic Vaccinia vector was then engineered to encode this novel, strongly Treg-depleting, checkpoint-blocking, anti-CTLA-4 antibody and GM-CSF (VVGM-ahCTLA4, BT-001). Viruses encoding a matching Treg-depleting mouse surrogate antibody were additionally generated, enabling proof-of-concept studies in syngeneic immune competent mouse tumor models.

Results Our studies demonstrate that intratumoral (i.t.) administration of VVGM-aCTLA4 achieved tumor-restricted CTLA-4 receptor saturation and Treg-depletion, which elicited antigen cross-presentation and stronger systemic expansion of tumor-specific CD8+ T cells and antitumor immunity compared with systemic anti-CTLA-4 antibody therapy. Efficacy correlated with FcgR-mediated intratumoral Treg-depletion and the reduction of exhausted CD8+ T cells. Remarkably, in a clinically relevant mouse model resistant to systemic immune checkpoint blockade, i.t. VVGM-aCTLA4 synergized with anti-PD-1 to reject “cold” tumors.

Conclusions Our findings demonstrate in vivo proof-of-concept for spatial restriction of strongly Treg-depleting, immune checkpoint blocking, vectorized anti-CTLA-4 as a highly effective and safe strategy to target CTLA-4 which is able to overcome current limitations of approved anti-CTLA-4 regimens. A clinical trial evaluating i.t. VVGM-ahCTLA4 (BT-001) alone and in combination with anti-PD-1 in metastatic or advanced solid tumors has commenced.

Ethics Approval All mouse experiments were approved by the local ethical committee for experimental animals (Malmö/Lunds djurförsöksetiska nämnd); at BioInvent under permit numbers 17196/2018 or 2934/2020; or at Transgene APAFIS Nr21622 project 2019072414343465 and performed in accordance with local ethical guidelines.

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