Introduction

Many strategies are being implemented to develop companion diagnostic tests in addition to adjuvant / combination therapies in order to bolster responses to immunotherapies.  In 2018, only an estimated 12% of all advanced stage cancer patients in the U.S. would respond to checkpoint inhibitor treatment; notably, this percentage includes patients of all cancer indications [1].  One promising, although nascent, strategy is to administer immune checkpoint inhibitors (ICI) in combination with oncolytic viruses; multiple studies have demonstrated that oncolytic viruses may increase response to checkpoint inhibitor therapies [2-4].Oncolytic viruses (OVs) have not been top of mind in the world of cancer treatment as a routine clinical option.  Nevertheless, oncolytic viruses are recently (e.g., in the last ~4-5 years) gaining traction for their promising therapeutic potential, especially when used in combination with checkpoint inhibitors. Researchers began to gather momentum around oncolytic viruses in the late 20th century [5]; however, to date, only one oncolytic viral therapy has gained FDA approval (IMLYGIC [6], a Herpes Simplex Virus Type 1 by Amgen).  In Amgen’s wake, many other companies (Candel Therapeutics [7], Cold Genesys [8], Vyriad [9], et al.) are engaged in clinical trials with oncolytic viruses.  Some larger biopharmaceutical companies (Merck [10], Bristol Myers Squibb [11], Pfizer [12], AstraZeneca [13], et al.) have entered into collaboration agreements with and / or acquired oncolytic viral companies.  These collaboration efforts strive to improve the efficacy of immune checkpoint inhibitors through combination with oncolytic viruses.  Noteworthy monetary investments, trial initiations, and partnering agreements hint that leaders in the I / O space recognize the clinical and commercial viability of these combination approaches.  Here, we highlight an emerging market for oncolytic viruses: they may increase the efficacy of checkpoint inhibitors.

Important Highlights

Advances in precision medicine (e.g., improved diagnostics and personalized therapies) will enhance the efficacy of checkpoint inhibitors as well as oncolytic viruses, opening windows of opportunity for combination therapies.  These new developments make the field interesting and important for the following reasons:

• Thousands of patients are enrolled in ongoing trials for oncolytic viruses; approximately 85% of such patients are enrolled in clinical trials for a combination therapy of ICIs and OVs, hinting at the clinical impact of a synergistic therapy
• Two stage III trials with T-Vec in combination with Pembrolizumab (Keytruda) hint at a potentially near-term successful synergistic therapy for those with late-stage melanoma; a combination approach would increase therapeutic options for patients with advanced, late-stage melanoma
• Combination approaches may open the door for oncolytic viruses to enter the clinic even though only one oncolytic virus is on the market to date due to their limited success as monotherapies

Method of Action (Figure 1 [14]) [caption id="attachment_4593" align="alignnone" width="850"]

Figure 1. Oncolytic viruses are common viruses (e.g., Herpes Simplex Virus, Vaccinia Virus, Measles) that are genetically modified and engineered to target cancer cells; although different genetic modifications slightly alter the mechanism of action, the following is the general mechanism of action. Genetic modifications allow these viruses to selectively replicate inside cancer cells by relying on cancer cells’ distinctive properties (e.g., growth signaling mechanisms, unrestricted replication, unresponsiveness to growth signaling repressive mechanisms) and hijacking the cells’ replication machinery.  After sufficient replication, the oncolytic virus lyses the cancer cells and spreads the viral genetic material to other tumor cells, creating a systemic anti-cancer response. The oncolytic virus then has two immune effects in the tumor microenvironment: 1) Virus-infected tumor cells trigger cytokine signaling to induce an innate immune response, and 2) When the cancer cell lyses, tumor antigens are released which activate an adaptive immune response. Figure courtesy of Davola et al., 2019 (DOI: 10.1080/2162402X.2019.1596006)[/caption]

Clinical Trials Investigating the Combination of OVs and ICIs

Continued and increasing momentum surrounding this combination approach is evidenced by investments in clinical trials (e.g., number of clinical trials and patients enrolled in clinical trials). Throughout 2020, there were 185 total oncolytic viruses in development and ~65 in clinical trials [15].  Currently, there are ~70 ongoing clinical trials and ~4,100 patients enrolled in clinical trials with OVs; ~3,500 (~85%) of these patients are enrolled in 34 trials evaluating OVs in combination with immune checkpoint inhibitors. 5 clinical trials with start dates in 2019  focused on the combination approach (ICI + OV), and 10 such combination trials (ICI + OV)  trials had start dates in 2020.  Already, there are 5 clinical trials with start dates in 2021 to investigate the combination. Interestingly, there were 7 such clinical trials with start dates in 2017, but 5 of these are still either active or recruiting. We believe that results from these studies may increase momentum around a combination approach.  The following graph (Figure 2) demonstrates the year by year increase in the number of clinical trials focused on OVs (split by OV alone, OV + other, or OV + ICI). Additionally, Figure 3 highlights the current (Q1 2021) enrollment demographics by OV therapy type (OV alone, OV + other, or OV + ICI).  As demonstrated by both figures, there has been significant investment in the combination therapy approach with an ICI.[caption id="attachment_4598" align="alignleft" width="1024"]

Figure 2[/caption][caption id="attachment_4599" align="alignleft" width="1024"]

Figure 3[/caption]

OVs have had limited success as monotherapies

Clinical trials have generally supported the safety of oncolytic viruses, but their efficacy as monotherapies has been limited in ways which may be improved by a combination approach.  Oncolytic viruses have demonstrated tolerable toxicities, mild adverse events (e.g., a low number of severe adverse events like neurotoxicity), and minimal mortality.  Nevertheless, technological hurdles have inhibited their ability to create a robust anti-tumor response.  Some of these technological failures include: 1) transient or localized viral replication (rather than systemic spread), 2) tumor insensitivity to viruses after continual exposure, 3) pre-existing immunity to common viruses due to pre-exposure, and 4) inefficient OV delivery (e.g., intratumoral delivery is only possible for accessible tumor types). Technological advancements aim to address these issues while maintaining the current safety profile of OVs, but a combination therapy approach may be critical to ultimate success[16].

OVs can overcome CD8+ and IFNg immune escape, boosting CPI efficacy in many resistant patients

Oncolytic viruses harbor an intrinsic immunotherapeutic ability which, when paired with checkpoint inhibitors, may become their most powerful asset.  Past studies have indicated that higher levels of pre-existing anti-tumor T cells in the tumor microenvironment (TME) correlate with better responses to checkpoint inhibitors [17, 18].  This correlation opens the pathway for a synergistic therapy between oncolytic viruses and checkpoint inhibitors. OVs have demonstrated the ability to modify the TME immune landscape and reverse immune tolerance to cancer cells, leading to a downstream adaptive immune response and the activation of naïve CD8+ T cells.  Furthermore, OVs tend to stimulate IFN release in the TME which causes tumor cells to upregulate PD-L1, enhancing potential responses to anti-PD-L1 checkpoints[19]. In summary, OVs can turn a “cold tumor” into a “hot tumor,” increasing the tumor’s susceptibility to treatment (see Figure 4).[caption id="attachment_4592" align="alignleft" width="745"]

Figure 4. Oncolytic Virus’ Mechanism of Action: Turning a “Cold Tumor” into a “Hot Tumor” Figure courtesy of Oh et al., 2020 (DOI: 10.3390/ijms21207743)[/caption]

Current / trials with oncolytic viruses used in combination with checkpoint inhibitors

Summary

As noted, oncolytic viruses have had limited success in cancer treatment. Nevertheless, their full therapeutic potential remains untapped.  As technologies develop, oncolytic viruses may play a greater role in immunotherapy, especially when used as combination therapies with checkpoint inhibitors.  A synergistic relationship between immune checkpoint inhibitors and oncolytic viruses may lead both therapies to reach a broader patient population with greater success.Our 3 key takeaways from this research are as follows:

• Oncolytic viruses are gaining interest as emerging clinical assets as evidenced by ~4,100 patients enrolled in ongoing clinical trials as well as acquisitions by / collaborations with major pharmaceutical companies (e.g., Merck, BMS, Pfizer, AZN)
• While monotherapy approaches for oncolytic viruses are still key for feasibility, ~85% of oncolytic viruses trials are in combination with a checkpoint inhibitor therapy
• ~34 ongoing clinical trials are exploring checkpoint inhibitors and oncolytic viruses in combination settings with >3,000 patients enrolled in these trials, especially in solid tumors; of note, <15 trials are phase II+, indicating that near-term registration is unlikely, but we are hopeful about the ultimate success of the combination approach for approved indications

‍

References

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503493/

[2] https://pubmed.ncbi.nlm.nih.gov/28886381/

[3] https://pubmed.ncbi.nlm.nih.gov/28238174/

[4] https://www.oncolyticsbiotech.com/press-releases/press-releases/detail/526/oncolytics-and-solti-report-clinical-synergy-of-pelareorep

[5] https://www.cancer.gov/news-events/cancer-currents-blog/2018/oncolytic-viruses-to-treat-cancer

[6] https://www.imlygic.com/

[7] https://www.candeltx.com/pipeline/

[8] https://www.cgoncology.com/pipeline/#overview

[9] https://vyriad.com/clinical-program/

[10] https://www.biospace.com/article/merck-drops-394-million-to-acquire-virus-based-cancer-company-viralytics/

[11] https://news.bms.com/news/details/2016/Bristol-Myers-Squibb-Signs-Exclusive-Worldwide-License-Agreement-with-PsiOxus-Therapeutics-for-NG-348-an-Armed-Oncolytic-Virus-to-Address-Solid-Tumors/default.aspx

[12] https://www.pfizer.com/news/press-release/press-release-detail/pfizer_and_western_oncolytics_announce_immuno_oncology_research_collaboration_to_investigate_novel_oncolytic_virus_technology

[13] https://www.targovax.com/en/collaboration-trials/

[14] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516024

[15] https://media.nature.com/original/magazine-assets/d41573-020-00166-1/d41573-020-00166-1.pdf

[16] https://www.jci.org/articles/view/122287

[17] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896787/

[18] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064638/

[19] https://www.jci.org/articles/view/122287

‍