Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors
Background Immune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, a majority of patients with cancer including those with poorly immune infiltrated ‘cold’ tumors are resistant to currently available ICB therapies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)...
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BMJ Publishing Group
2022-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/1/e003488.full |
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| author | Laetitia Fend Eric Quemeneur Monika Semmrich Jean-Baptiste Marchand Matilda Rehn Nathalie Silvestre Linda Mårtensson Johann Foloppe Ingrid Teige Björn Frendeus Petra Holmkvist Carolin Svensson Christelle Remy Patricia Kleinpeter Jules Deforges Fred Junghus Kirstie L Cleary Mimoza Bodén |
| author_facet | Laetitia Fend Eric Quemeneur Monika Semmrich Jean-Baptiste Marchand Matilda Rehn Nathalie Silvestre Linda Mårtensson Johann Foloppe Ingrid Teige Björn Frendeus Petra Holmkvist Carolin Svensson Christelle Remy Patricia Kleinpeter Jules Deforges Fred Junghus Kirstie L Cleary Mimoza Bodén |
| author_sort | Laetitia Fend |
| collection | DOAJ |
| description | Background Immune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, a majority of patients with cancer including those with poorly immune infiltrated ‘cold’ tumors are resistant to currently available ICB therapies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is one of few clinically validated targets for ICB, but toxicities linked to efficacy in approved αCTLA-4 regimens have restricted their use and precluded full therapeutic dosing. At a mechanistic level, accumulating preclinical and clinical data indicate dual mechanisms for αCTLA-4; ICB and regulatory T cell (Treg) depletion are both thought to contribute efficacy and toxicity in available, systemic, αCTLA-4 regimens. Accordingly, strategies to deliver highly effective, yet safe αCTLA-4 therapies have been lacking. Here we assess and identify spatially restricted exposure to a novel strongly Treg-depleting, checkpoint-blocking, vectorized αCTLA-4, as a highly efficacious and potentially safe strategy to target CTLA-4.Methods A novel human IgG1 CTLA-4 antibody (4-E03) was identified using function-first screening for monoclonal antibodies (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, αCTLA-4 antibody or a matching surrogate antibody, and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (VVGM-αCTLA-4).Results The identified 4-E03 antibody showed significantly stronger Treg depletion, but equipotent checkpoint blockade, compared with clinically validated αCTLA-4 ipilimumab against CTLA-4-expressing Treg cells in a humanized mouse model in vivo. Intratumoral administration of VVGM-αCTLA-4 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 αCTLA-4 antibody therapy. Efficacy correlated with FcγR-mediated intratumoral Treg depletion. Remarkably, in a clinically relevant mouse model resistant to systemic ICB, intratumoral VVGM-αCTLA-4 synergized with αPD-1 to reject cold tumors.Conclusion Our findings demonstrate in vivo proof of concept for spatial restriction of Treg depletion-optimized immune checkpoint blocking, vectorized αCTLA-4 as a highly effective and safe strategy to target CTLA-4. A clinical trial evaluating intratumoral VVGM-αhCTLA-4 (BT-001) alone and in combination with αPD-1 in metastatic or advanced solid tumors has commenced. |
| format | Article |
| id | doaj-art-715bfd92355a4c01a650b6be33e6abb9 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-715bfd92355a4c01a650b6be33e6abb92025-02-09T21:35:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-01-0110110.1136/jitc-2021-003488Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumorsLaetitia Fend0Eric Quemeneur1Monika Semmrich2Jean-Baptiste Marchand3Matilda Rehn4Nathalie Silvestre5Linda Mårtensson6Johann Foloppe7Ingrid Teige8Björn Frendeus9Petra Holmkvist10Carolin Svensson11Christelle Remy12Patricia Kleinpeter13Jules Deforges14Fred Junghus15Kirstie L Cleary16Mimoza Bodén17Department of Research, Transgene SA, Illkirch-Graffenstaden, FranceDepartment of Research, Transgene SA, Illkirch-Graffenstaden, France1BioInvent International, Lund, SwedenTransgene SA, Illkirch-Graffenstaden, France1BioInvent International AB, Lund, SwedenTransgene SA, Illkirch-Graffenstaden, France1BioInvent International, Lund, SwedenTransgene SA, Illkirch-Graffenstaden, FranceDepartment of Research, BioInvent International AB, Lund, Sweden1BioInvent International, Lund, Sweden1BioInvent International, Lund, Sweden1BioInvent International, Lund, SwedenTransgene SA, Illkirch-Graffenstaden, FranceTransgene SA, Illkirch-Graffenstaden, FranceTransgene SA, Illkirch-Graffenstaden, FranceDepartment of Research, BioInvent International AB, Lund, SwedenAntibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK1BioInvent International, Lund, SwedenBackground Immune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, a majority of patients with cancer including those with poorly immune infiltrated ‘cold’ tumors are resistant to currently available ICB therapies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is one of few clinically validated targets for ICB, but toxicities linked to efficacy in approved αCTLA-4 regimens have restricted their use and precluded full therapeutic dosing. At a mechanistic level, accumulating preclinical and clinical data indicate dual mechanisms for αCTLA-4; ICB and regulatory T cell (Treg) depletion are both thought to contribute efficacy and toxicity in available, systemic, αCTLA-4 regimens. Accordingly, strategies to deliver highly effective, yet safe αCTLA-4 therapies have been lacking. Here we assess and identify spatially restricted exposure to a novel strongly Treg-depleting, checkpoint-blocking, vectorized αCTLA-4, as a highly efficacious and potentially safe strategy to target CTLA-4.Methods A novel human IgG1 CTLA-4 antibody (4-E03) was identified using function-first screening for monoclonal antibodies (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, αCTLA-4 antibody or a matching surrogate antibody, and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (VVGM-αCTLA-4).Results The identified 4-E03 antibody showed significantly stronger Treg depletion, but equipotent checkpoint blockade, compared with clinically validated αCTLA-4 ipilimumab against CTLA-4-expressing Treg cells in a humanized mouse model in vivo. Intratumoral administration of VVGM-αCTLA-4 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 αCTLA-4 antibody therapy. Efficacy correlated with FcγR-mediated intratumoral Treg depletion. Remarkably, in a clinically relevant mouse model resistant to systemic ICB, intratumoral VVGM-αCTLA-4 synergized with αPD-1 to reject cold tumors.Conclusion Our findings demonstrate in vivo proof of concept for spatial restriction of Treg depletion-optimized immune checkpoint blocking, vectorized αCTLA-4 as a highly effective and safe strategy to target CTLA-4. A clinical trial evaluating intratumoral VVGM-αhCTLA-4 (BT-001) alone and in combination with αPD-1 in metastatic or advanced solid tumors has commenced.https://jitc.bmj.com/content/10/1/e003488.full |
| spellingShingle | Laetitia Fend Eric Quemeneur Monika Semmrich Jean-Baptiste Marchand Matilda Rehn Nathalie Silvestre Linda Mårtensson Johann Foloppe Ingrid Teige Björn Frendeus Petra Holmkvist Carolin Svensson Christelle Remy Patricia Kleinpeter Jules Deforges Fred Junghus Kirstie L Cleary Mimoza Bodén Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors Journal for ImmunoTherapy of Cancer |
| title | Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors |
| title_full | Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors |
| title_fullStr | Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors |
| title_full_unstemmed | Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors |
| title_short | Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors |
| title_sort | vectorized treg depleting αctla 4 elicits antigen cross presentation and cd8 t cell immunity to reject cold tumors |
| url | https://jitc.bmj.com/content/10/1/e003488.full |
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