Intratumoral Immunotherapy-Update 2019

Abstract

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications. IMPLICATIONS FOR PRACTICE: This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

Keywords: Immune checkpoint inhibitors; Intratumoral immunotherapies; Melanoma; OPTiM; Talimogene laherparepvec.

Figure 1

History of intratumoral therapies. Abbreviations: GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; HNC, head and neck cancer; T‐VEC, talimogene laherparepvec.

Figure 2

Proposed mechanisms of action for T‐VEC and effect of T‐VEC on immune cell populations. Abbreviations: GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; T‐VEC, talimogene laherparepvec. Image courtesy of Amgen Inc.

Figure 3

Talimogene laherparepvec (T‐VEC) injection procedures and recommended dosing schedule. Illustration of T‐VEC administration for (A) cutaneous lesions, (B) subcutaneous lesions, and (C) nodal lesions. A new needle is used for each injected lesion. (D): After injection, the injection site and surrounding area should be swabbed with alcohol and an absorbent pad and dry occlusive dressing should be applied. (E): The exterior of the occlusive dressing should also be swabbed with alcohol.

Figure 4

Duration of response in responders from OPTiM and T‐VEC combination trials. Duration of response for responders in the OPTiM trial (A) and combination trials of T‐VEC and pembrolizumab (B) (MASTERKEY‐265 phase 1b) or ipilimumab (C). Duration of response was defined as the longest period of response from entering response to first documented evidence of patient no longer meeting criteria for response. Response was evaluated by central Endpoint Assessment Committee in OPTiM and by investigators in MASTERKEY‐265 phase 1b and the study of T‐VEC plus ipilimumab. Abbreviations: CR, complete response; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; PR, partial response; T‐VEC, talimogene laherparepvec. Sources: Figure 4A was published in Kaufman et al., 2017 [88], which is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) that permits unrestricted use, distribution, and reproduction in any medium. Figure 4B and 4C courtesy of Amgen Inc. (data on file).

Figure 5

Overall survival and association between durable response and overall survival in OPTiM. Kaplan‐Meier plots of overall survival in the OPTiM ITT population (A), and in patients who achieved a durable response vs. patients who did not achieve durable response prior to landmark times of 9 months (B), 12 months (C), and 18 months (D) from randomization. Abbreviations: CI, confidence interval; DR, durable responder; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; HR, hazard ratio; ITT, intention to treat; NE, not estimable; OS, overall survival; T‐VEC, talimogene laherparepvec. Sources: Figure 5A has been adapted from: Kaufman HL, Andtbacka RHI, Collichio FA et al. Primary overall survival (OS) from OPTiM, a randomized phase 3 trial of talimogene laherparepvec (T‐VEC) versus subcutaneous (SC) granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) for the treatment of unresected stage IIIB/C and IV melanoma. Oral presentation from the 2014 Annual Meeting of the American Society of Clinical Oncology; May 30–June 4, 2014; Chicago, IL. Figure 5B–D were published in Kaufman et al., 2017 [88], which is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) that permits unrestricted use, distribution, and reproduction in any medium.