How should we combine oncolytic virotherapy with other agents?


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Kevin Harrington1
1The Institute of Cancer Research

Abstract

Talimogene laherparepvec (T-VEC) is a genetically-modified herpes simplex virus type 1-derived injectable oncolytic virus that is selectively replication-competent in tumour cells (especially those with MAPK pathway activation). It expresses human granulocytemacrophage colony-stimulating factor as an immunostimulatory cytokine1. T-VEC is well tolerated. In a phase 3 trial in 436 pts with unresected stage IIIB-IV melanoma (the OPTiM trial2), intralesional T-VEC improved durable response rate (continuous partial response [PR] or CR ≥6 months; primary endpoint) from 2% to 16% vs subcutaneous recombinant GM-CSF. T-VEC was approved by the US FDA and EMA in October 2015 and by NICE in 2016. Subsequent phase Ib studies of T-VEC and immuno-oncology (IO) agents (ipilimumab3 and pembrolizumab4) have now completed recruitment. Each of these studies has demonstrated tolerable toxicity profiles (with no dose-limiting toxicities) and impressive anti-tumour efficacy. Detailed data from these studies will be discussed and plans for subsequent phase III evaluations of T-VEC plus pembrolizumab (in melanoma and head and neck cancer) will be presented.

Another oncolytic virotherapy (Coxsackievirus A21 (CVA-21), CAVATAKTM) is also under development and this has achieved impressive responses by intratumoural delivery (Phase II CALM study). In addition, CVA-21 has been administered by intravenous injection in the phase I STORM study. Each of these approaches can be combined with immune checkpoint inhibition (ICPI) and plans for such studies will be discussed.

In addition to opportunities for synergistic interactions between oncolytic immunotherapies and IO agents, combination regimens with molecularly-targeted agents and/or radiotherapy have significant potential. Studies of oncolytic reovirus (Reovirus Type 3 Dearing, Pelareorep) in combination with other modalities will be presented to illustrate these possibilities.

  1. Liu BL, et al. Gene Ther 2003;10:292–303.
  2. Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.
  3. Puzanov I, et al. J Clin Oncol 2016;34:2619-26.
  4. Long G, et al. ECC 2015:abstract 24LBA.