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TG4001 Therapeutic Vaccination Plus Avelumab-Mediated PD-L1 Blockade Improves Tumour Microenvironment in HPV-Positive Malignancies

This combination changes “cold” tumour microenvironments to “hot” in Human Papillomavirus-positive malignancies
12 Dec 2020
Cancer Immunology and Immunotherapy

Therapeutic Vaccination with TG4001 administered with avelumab in patients with various Human Papillomavirus (HPV)-positive malignancies, results in a more favourable tumour microenvironment (TME) with increased effector cell infiltrates that drives an anti-tumour response. Investigators presented these findings at the ESMO Immuno-Oncology Virtual Congress 2020, held from 9 to 12 December 2020.

Christophe Le Tourneau of the Department of Drug Development and Innovation, Institut Curie in Paris, France explained that the immune rejection of tumours is contingent upon the development of a specific immune response and presence of a favourable TME.

Professor Le Tourneau and colleagues evaluated whether the TG4001 vaccine, which expresses HPV16 E6 and E7 proteins based on a recombinant Modified Vaccinia Ankara vaccine combined with the anti-PD-L1 monoclonal antibody, avelumab, could provide priming of the TME and enhanced anti-tumour activity.

The study (NCT03260023) enrolled 34 patients with various recurrent/metastatic HPV-positive cancers; of these, 15 patients had HPV16-positive anal, 8 had oropharyngeal, 6 had cervical, and 5 patients had vulvar/vaginal cancer. All patients received 5 x107 plaque forming units (PFU) by subcutaneous injection each week for 6 weeks, every 2 weeks for 6 months, and every 12 weeks thereafter plus intravenous avelumab at 10 mg/kg every 2 weeks.

Tissue and peripheral blood mononuclear cell (PBMC) samples were collected at baseline and on study day 43. Measurement of the T-cell response to HPV antigens was done using ex-vivo IFNγ-ELI SPOT on PBMCs; PD-L1 expression, as well as CD3- and CD8-positive infiltrates were evaluated by immunostaining of tumour samples, and changes in gene expression were measured using NanoString technology.

Strong T-cell activity was observed and maintained

Of the 34 vaccinated patients, one patient demonstrated complete response (CR) and 7 patients achieved partial response per RECIST v1.1.

TG4001-Therapeutic-Vaccination-Plus-Avelumab-Mediated-PD-L1-Blockade-Improves-Tumour-Microenvironment-in-HPV-Positive-Malignancies

Activity of TG4001 plus avelumab in HPV-positive malignancies.

© Christophe Le Tourneau.

Of the 11 patients that were evaluable for ELISPOT, 7 developed reactive T cells against E6, E7 or both antigens after vaccination.

By day 43, the patient achieving CR showed an intense T cell response against E6 and E7, which was maintained for another 6 months, and was consistent with sustained disease control.

The patients mounting a clinical response had a higher level of baseline PD-L1 expression compared to non-responders. Responders also showed higher median CD3 cell infiltrates of 470 versus 200 per mm² in non-responders, as well as higher median CD8 cell infiltrates of 238 versus 92 per mm², respectively. The infiltrates tended to increase during treatment and were accompanied by strong changes of the tumour transcriptomic profile by day 43. This profile demonstrated increased expression of effector T cell activation cascades; specifically, CD3G was increased by 13 fold, IL21R by 17-fold, and IFNG was increased by 9-fold as compared to baseline.

The Immunosign gene signature was applied to provide an index of “cold” or “hot” TME profile, which indicated that, at baseline, 57% of patients had a “hot” TME profile that was increased to 100% of patients at day 43 of treatment.

Conclusions

Based upon these findings, the authors were able to conclude that TG4001 vaccination together with PD-L1 blockade with avelumab led to the development of specific immunity and TME transformations in patients with HPV-positive cancer.

They further suggest that these events have the potential of improving clinical benefit.

Funding was reported from Transgene and Merck Serono.

Reference

63MO – Le Tourneau C, Cassier P, Rolland F, et al. TG4001 therapeutic vaccination combined with PD-L1 blocker avelumab remodels the tumor microenvironement (TME) and drives antitumor responses in human papillomavirus (HPV)+ malignancies. ESMO Immuno-Oncology Virtual Congress 2020 (9-12 December).

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