30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)
- Poster presentation
- Open Access
Phase II calm extension study: Coxsackievirus A21 delivered intratumorally to patients with advanced melanoma induces immune-cell infiltration in the tumor microenvironment
Journal for ImmunoTherapy of Cancer volume 3, Article number: P343 (2015)
CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Following intratumoral (IT) injection, CVA21 preferentially infects ICAM-1 expressing tumor cells, resulting in viral replication, cell lysis, and a systemic anti-tumor immune response. The Phase II CALM study investigated the efficacy and safety of IT CVA21 in pts with advanced melanoma. The primary endpoint of the study was achieved with 22 of 57 (38.6%) evaluable pts with durable responses observed in both injected and uninjected melanoma metastases, suggesting the generation of significant host anti-tumor responses. Pre-clinical studies in an immune-competent mouse model of melanoma revealed that combinations of intratumoral CAVATAK and anti-PD-1 or anti-CTLA-4 mAbs mediated significantly greater anti-tumor activity compared to use of either agent alone. Here we report on a continuation study aimed at understanding the immune mediated effects of CVA21.
To further elucidate the nature of the systemic anti-tumor responses, a CALM study (NCT01227551) extension cohort of 13 pts received up to 3 x 108 TCID50 CVA21 IT on study days 1,3,5 and 8 and then every three weeks for a further 6 injections. Sequential tumor biopsies of both injected and uninjected lesions were monitored for levels of viral replication and evidence of viral-induced immune activation within the tumor micro-environment. Serial serum samples were monitored for viral loads, anti-CVA21 neutralizing antibody (nAb) and levels of immune-inflammatory cytokines.
CVA21 administration was shown in 5 of 6 cases to induce increases in immune cell infiltrates within the tumor microenvironment, in particular CD8+cells and increased expression of PD-L1+ cells as assessed by multispectral imaging. Reconstitution of immune cell infiltrates was observed in 4 of 4 of CVA21 treated lesions from patients failing treatment with single or double-line immune-checkpoint blockade. Analysis of 4 pre- and post-treatment biopsy samples by NanoString digital RNA counting identified sizable up-regulation of a number of immune modulation elements, including a Th1-gene shift, with increases in interferon-induced genes.
Intralesional administration of CVA21 can notably influence the dynamics of the tumor micro-environment as evidenced by increases in immune cell infiltrates and immune-related response genes. Our observation that CVA21 can reconstitute immune cell infiltrates in lesions resistant to immune-checkpoint blockade provides a strong rationale for the investigation of the sequential or concurrent administration of CVA21 and T cell checkpoint antibodies. A clinical trial combining CVA21 with anti-CTLA-4 is underway and other combination studies are planned.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Andtbacka, R.H., Curti, B.D., Hallmeyer, S. et al. Phase II calm extension study: Coxsackievirus A21 delivered intratumorally to patients with advanced melanoma induces immune-cell infiltration in the tumor microenvironment. j. immunotherapy cancer 3 (Suppl 2), P343 (2015). https://doi.org/10.1186/2051-1426-3-S2-P343
- Tumor Microenvironment
- Advanced Melanoma
- Immune Cell Infiltrate
- Serial Serum Sample
- Intralesional Administration