The Need to do Better
The treatment of certain cancers has improved markedly over the past decade. Whereas many cancer treatments were historically limited to surgical removal, cytotoxic chemotherapy and/or radiation, recent advances target specific genetic changes in individual tumors or redirect the patient’s immune system, particularly T cells, to eliminate tumors to improve outcomes. Unfortunately, most patients do not respond to or relapse following treatment with these therapies.
While these therapies have advanced the treatment of cancer for some patients, many are still underserved, and therapies with improved clinical outcomes are still desperately needed.
The Promise of Viral Immunotherapies
The goal of immuno-oncology therapy is to harness an individual’s immune system and better enable it to identify, attack and kill tumor cells – and to form long-term immunologic memory against such tumors.
We believe that the best way to significantly improve outcomes for cancer patients is to stimulate not only T cells, as has been the focus of approved immune checkpoint inhibitors and other recent advances in immuno-oncology, but also additional key immune cells within the innate and adaptive immune systems.
We believe viral immunotherapies are the most promising modality available today to activate multiple arms of the immune system and improve outcomes for patients.
A Unique Therapeutic Approach
Viral immunotherapies have several properties that differentiate this class from other anti-tumor therapies and make them particularly attractive additions to today’s anti-cancer arsenal.
1. Selectively kill tumor cells via immunogenic cell death
2. Create an inflammatory state that turns cold tumors hot
When tumor cells die following viral replication, the cells release tumor-specific antigens and danger signals, which activate the innate immune system and promote inflammation within the tumor microenvironment. This, in turn, attracts both innate and adaptive immune cells to that area. Viral immunotherapies have been shown in the clinic to transform so-called cold tumors, with low numbers of infiltrated immune cells, into hot tumors, with high numbers of infiltrated immune cells, which are more likely to respond to checkpoint inhibitors.
3. Cause the release and presentation of a greater breadth of tumor-specific antigens
The breadth of antigens that are presented by viral immunotherapy-induced tumor lysis, or tumor cell death, is far greater than that of other anti-tumor vaccine approaches that rely on single antigens or small collections of neoantigens. These antigens can then be presented by the recruited innate immune cells, such as macrophages and dendritic cells, to cells of the adaptive immune system to stimulate highly effective antigen-specific immunity.
By activating the adaptive immune response, anti-tumor T cells can then identify and attack all tumors in the body in addition to forming immunologic memory, which can provide patients with durable protective immunity.
4. Express transgenes within the tumor microenvironment that encode for immunostimulatory proteins
Viruses can be engineered to carry transgenes directly into tumors where they can be expressed in high concentrations. These transgenes can encode immunostimulatory cytokines, immune checkpoint antibodies and other proteins that can further amplify anti-tumor immune responses. The ability of viral immunotherapies to deliver potent immunostimulatory factors directly to tumors with minimal systemic exposure represents a powerful method of amplifying the initial immune response by both stimulating the infiltrating immune cells and preventing their suppression in tumors, leading to improved outcomes for cancer patients.
At Oncorus, we are advancing two platforms, our oncolytic Herpes Simplex Virus (oHSV) Platform for intratumorally administered viral immunotherapies, and our Synthetic viral RNA (vRNA) Platform for intravenously (IV) administered viral immunotherapies. Across both platforms, and a resulting pipeline of viral immunotherapies, we are striving to treat a broad spectrum of cancers to bring the potential of this therapeutic class to as many patients as possible.
Our oHSV Platform
Directly Targeting Tumors through Intratumoral Injection
Herpes Simplex Virus has emerged as the leading viral vector for immunotherapy. We have designed our proprietary oncolytic Herpes Simplex Virus (oHSV) Platform to develop improved viral immunotherapies that overcome the limitations of potency and the ability to stimulate anti-tumor immunity – both of which are challenges that have been encountered by previous viral immunotherapies and other immuno-oncology therapies.
We are using our oHSV Platform to develop viral immunotherapies that can be directly administered into a tumor, resulting in high local concentrations of the therapeutic agent, as well as low systemic exposure to the therapy, which we believe could potentially limit systemic toxicities.
We intend to advance multiple therapies derived from our oHSV Platform to address a spectrum of tumor types. We are developing our lead product candidate, ONCR-177, an intratumorally administered oHSV viral immunotherapy for the treatment of multiple solid tumor cancers. We have additional oHSV Platform-derived viral immunotherapy product candidates in earlier stage development, including ONCR-GBM to specifically target brain cancer, including glioblastoma multiforme.
Designed to Enhance Potency and Balance Safety
Our oHSV Platform is designed to deliver next-generation viral immunotherapy impact by improving upon three basic characteristics of this therapeutic class to enhance potency without sacrificing safety.
Greater capacity to encode transgenes to drive systemic immunostimulatory activity
Using our proprietary technology, we are developing oHSV-based product candidates with the ability to carry greater numbers of transgenes than viral immunotherapies that are either currently approved or in clinical development. This expanded payload capacity:
- Enables promotion of greater systemic immunostimulatory activity than could otherwise be achieved
- Enables combined delivery of immunostimulatory agents directly to tumors including those that cannot safely be dosed in patients due to systemic toxicities, such as IL-12
Retention of full replication competency to enable high tumor-killing potency
Using our proprietary oHSV Platform, we are developing oHSV-based viral immunotherapy product candidates that retain their full ability to replicate in tumor cells.
In contrast, current oHSV-based viral immunotherapies that are either currently approved or in clinical development have introduced mutations which attenuate their replication competency in both normal and tumor tissues to limit toxicity. We believe this has the effect of lowering the potency of the virus in tumor cells and trading off potency for safety.
Orthogonal safety strategies to restrict viral activity to tumor cells
Our oHSV Platform incorporates two highly innovative approaches to allow for tumor-specific replication, meaning we limit viral activity to tumor cells while sparing normal tissues.
- Use of microRNA, or miR, sequences. We insert gene regulatory elements known as miR target sequences within the genomes of viruses. The miRs complementary to these target sequences are primarily found only in normal tissues and not in tumor tissues.
- Mutate the HSV-1 protein, UL37. We have engineered a proprietary mutation in a HSV-1 protein, known as UL37, which eliminates the virus’ ability to transport, replicate and establish latency inside neurons.
Our lead oHSV viral immunotherapy candidate, ONCR-177, currently in Phase 1 clinical study, is designed to mount a powerful, multidimensional attack on cancer; it induces immunogenic cancer cell death and ignites innate and adaptive immunity to drive a lasting and systemic anti-tumor response. In addition to its oncolytic activity, ONCR-177 is armed with five immunostimulatory transgenes (IL-12, CCL4, FLT3LG, anti-PD-1 and anti-CTLA-4).
Our Synthetic vRNA Platform
Repeat IV Administration of Viral Immunotherapies
There has been a notable rise in the development and approval of RNA-based vaccines, most prominently for COVID-19, and therapeutics for certain rare diseases. However, to date, there are no approved RNA-based cancer therapies.
The IV administration of viral immunotherapies is an attractive approach for improving the standard of care for many oncology patients because it allows for all tumors in a patient, including micro-metastases that are sometimes difficult to detect and treat, to be treated directly.
In addition, it allows for potential treatment of certain tumors, such as those of the lung, that are less amenable to repeat intratumoral injection of anti-cancer therapies for safety and feasibility reasons.
To date, however, the therapeutic benefit of viroimmunotherapy has been limited to intratumoral administration, restricting the application of this modality. In addition, past investigational programs that utilized IV-administered natural oncolytic viruses faced the challenge of neutralizing antibodies which is efficacy limiting in our preclinical models.
Our proprietary IV-delivered Synthetic vRNA Immunotherapy Platform involves a novel, highly innovative combination of RNA- and OV-based modalities, enabling the potential to deliver a new pillar in cancer therapy.
A Novel RNA-Based Viral Immunotherapy Strategy
Our pioneering IV-administered synthetic approach involves encapsulating the RNA genomes of viruses known to kill cancer cells (i.e., OVs) in a lipid (i.e., fat) nanoparticle (or LNP), creating a Synthetic vRNA immunotherapy.
This LNP delivery strategy, which is intended to be less immunogenic than a natural viral capsid, is designed to overcome the challenges caused by neutralizing antibodies that have limited the efficacy of previous industry efforts to administer viruses intravenously to treat tumors.
Once inside the tumor cells, and as is the case with other viral immunotherapies, these genomes replicate and generate a burst of infectious virions that then spread locally and infect and kill adjacent tumor cells.
Synthetic vRNA Immunotherapy Programs
Our lead synthetic vRNA immunotherapy programs, ONCR-021 and ONCR-788, are based on coxsackievirus A21 (CVA21) and Seneca Valley Virus (SVV), respectively. Both of these viruses have demonstrated acceptable safety and tolerability when virions have been administered intravenously in early clinical trials conducted by others, but where efficacy was likely limited by the subsequent development of neutralizing antibodies.
ONCR-021, ONCR-788 and any future synthetic vRNA immunotherapy product candidates to be developed from our Synthetic vRNA Platform will utilize shared formulation, regulatory and manufacturing strategies, allowing us to be more efficient in the development of subsequent product candidates.
Oncorus Publications & Presentations
ONCR-177, an oncolytic HSV-1 designed to potently activate systemic antitumor immunity
Cancer Immunology Research, December 22, 2020
Brian B Haines, Agnieszka Denslow, Peter Grzesik, Jennifer S Lee, Terry Farkaly, Jacqueline Hewett, Daniel Wambua, Lingxin Kong, Prajna Behera, Judith Jacques, Caitlin Goshert, Michael Ball, Allison Colthart, Mitchel H. Finer, Melissa W Hayes, Sonia Feau, Edward M. Kennedy, Lorena Lerner and Christophe Quéva. ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity. Cancer Immunology Research. December 22, 2020; DOI: 10.1158/2326-6066.CIR-20-0609
Design of an interferon-resistant oncolytic HSV-1 incorporating redundant safety modalities for improved tolerability
Molecular Therapy: Oncolytics, August 8, 2020
Edward M. Kennedy, Terry Farkaly, Peter Grzesik, Jennifer Lee, Agnieszka Denslow, Jacqueline Hewett, Jeffrey Bryant, Prajna Behara, Caitlin Goshert, Daniel Wambua, Ana De Almeida, Judith Jacques, Damian Deavall, James B. Rottman, Joseph C. Glorioso, Mitchell H. Finer, Brian B. Haines, Christophe Quéva, and Lorena Lerner. Molecular Therapy: Oncolytics, Vol 18, pages 476-490.; https://doi.org/10.1016/j.omto.2020.08.004
mONCR-177 oncolytic virotherapy stimulates anti-tumor response
ACCR Annual Meeting Virtual Meeting II, June 22 - 24, 2020
Development of ONCR-177, an armed oncolytic HSV-1 designed for potent and systemic stimulation of antitumor immunity
6th Annual Immuno-Oncology 360°, New York, New York, February 26 – 28, 2020
Design of ONCR-177 base vector, a next generation oncolytic herpes simplex virus type-1, optimized for robust oncolysis, transgene expression and tumor-selective replication
AACR Annual Meeting, Atlanta, Georgia, March 29 – April 3, 2019
Development of ONCR-148, a miR-attenuated oncolytic HSV-1 designed to potently activate antitumor T cell response
AACR Annual Meeting, Atlanta, Georgie, March 29 – April 3, 2019
Development of ONCR-NEP, a lipid nanoparticle delivered oncolytic virus capable of robust in situ amplification resulting in tumor lysis and regression
AACR Annual Meeting, Atlanta, Georgia, March 29 – April 3, 2019
Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma
JCI Insight, July 11, 2019
Hans-Georg Wirsching, Huajia Zhang, Frank Szulzewsky, Sonali Arora, Paola Grandi, Patrick J. Cimino, Nduka Amankulor, Jean S. Campbell, Lisa McFerrin, Siobhan S. Pattwell, Chibawanye Ene, Alexandra Hicks, Michael Ball, James Yan, Jenny Zhang, Debrah Kumasaka, Robert H. Pierce, Michael Weller, Mitchell Finer, Christophe Quéva, Joseph C. Glorioso, A. McGarry Houghton, and Eric C. Holland. Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma. JCI Insight. 2019;4(13):e128217. https://doi.org/10.1172/jci.insight.128217
Cooperation of oncolytic virotherapy with with VEGF-neutralizing antibody treatment in IDH wildtype glioblastoma depends on MMP9
Neuro-Oncology, December 2019
Hans-Georg Wirsching, Sonali Arora, Huajia Zhang, Frank Szulzewsky, Patrick J Cimino, Christophe Quéva, A McGarry Houghton, Joseph C Glorioso, Michael Weller, Eric C Holland, Cooperation of oncolytic virotherapy with VEGF-neutralizing antibody treatment in IDH wildtype glioblastoma depends on MMP9, Neuro-Oncology, Volume 21, Issue 12, December 2019, Pages 1607–1609, https://doi.org/10.1093/neuonc/noz145
Harrington, K., Freeman, D.J., Kelly, B. et al. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov 18, 689–706 (2019). https://doi.org/10.1038/s41573-019-0029-0
Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy
Ribas, A., Dummer, R., et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell 170, 1109-1119 (2017). https://www.cell.com/fulltext/S0092-8674(17)30952-2