Modulating the immune system to fight for good

The immune system is the body’s defense against pathogenic infections, but immune-mediated diseases such as cancer, diabetes, and allergic dermatitis arise from dysbiosis of the immune system. The immune system can work for you to prevent disease, go into overdrive to cause disease, or be tricked into not working like it should.

Immunotherapy, or the use of the body’s own immune system to combat disease, has truly defined the past decade of medical advancements. More than 20 million dogs and cats have immune diseases that could be ameliorated by using specific biologics to modulate the immune response. From monoclonal antibodies (mAbs) to personalized cancer immunotherapy to viruses loaded with immune-modulating properties, the field is rapidly growing and expanding.

Monoclonal antibodies

Therapeutic mAbs are highly targeted therapies that work by blocking specific cell-to-cell interactions. The first monoclonal antibody for humans was created in 1975 to prevent kidney transplant rejection by blocking CD3, a receptor found on T lymphocytes, to suppress the immune system.¹ Because T lymphocytes (commonly known as T cells) are the backbone of adaptive immunity, downregulating a T-cell response allows for a transplant to become successful — the body no longer has enough power to recognize the new organ as foreign.²

However, the major problem with the first mAb was that it was created from a mouse. Repeated administration of a mouse antibody into a human can cause an anti-mouse response within the body, leading to the potential for negative side effects.

Creating full speciated mAbs, or chimeric antibodies (the combination of mouse with the species of interest), is important to generate a specific response that will not lead to adverse events. So, “caninization,” “felinization,” and “equinization” are necessary in veterinary medicine to create safe and species-specific mAbs that will lead to an effective response. Balance here is key.

One of the most successful mAbs to date in veterinary medicine is Cytopoint (Zoetis Petcare), which was created to target interleukin-31, an inflammatory cytokine that is upregulated in allergic and atopic dermatitis.³ Cytopoint has become a game-changer for pet owners dealing with atopic dermatitis in their pets.

When it comes to cancer, mAbs for immune checkpoint inhibitors(ICIs) are moving toward becoming standard of care for human cancer treatment. From melanoma to non-small cell lung cancer, ICIs block the interaction of tumor cells that downregulate T cells within the tumor microenvironment. Specifically, when a tumor cell expresses PD-L1 (programmed death-ligand 1), it binds to PD-1 on the T cell, thus inactivating the T cell. Using an mAb against PD-L1 or PD-1 allows for the T cells to remain active within the microenvironment, which leads to tumor cell destruction.

In veterinary medicine, we are still a ways off from making ICI mAbs for cancer accessible and available. For one, there are only a subset of tumors and a subset of patients that overexpress PD-L1. Ensuring the PD-L1 expression level on these tumors requires either genomic tumor profiling or creation of specific diagnostic tests that would ensure potential efficacy for this treatment.

Second, creating a “caninized” version of an anti–PD-L1 therapy is both time-consuming and expensive. While over 4 million dogs are diagnosed with cancer each year, far fewer patients will have the expression levels of these antigens that will make commercializing ICIs a feasible business endeavor.

However, the specificity of therapeutic mAbs is truly astonishing, so as human science advances we will be sure to see more in the development pathway for cancer and osteoarthritis in veterinary medicine.

Personalized immunotherapies for cancer

Personalized cancer immunotherapies, such as autologous therapies or chimeric antigen receptor T cell (CAR-T) approaches, are growing within the veterinary field. Several veterinary-specific companies are focused on creating personalized cancer immunotherapies for pets.

Cancer is a disease of mutations. Each tumor, even within the same patient, is unique with regard to the array of epitopes expressed on each cell’s surface.⁴ Effective immunotherapies must encompass the diversity of cancer, as well as the diversity of the immune response of the tumor-bearing patient.

Autologous cancer immunotherapies are created for and used to treat a single patient. These activated T-cells, or “personalized vaccines,” can be provided back to the patient to stimulate an anti-tumor response. Instead of focusing on a single antigenic epitope, both methods allow for vaccination with an array of antigens. This is intended to develop multiple T-cell clones with different specificities and ligand affinities that generate a highly specific immune response.⁵

While personalized cancer immunotherapies in the veterinary market are still experimental, as regulated by the U.S. Department of Agriculture, they encompass a new generation of cancer therapy research in the veterinary market that is rapidly gaining traction.

Oncolytic viruses

One of the newest areas of immunotherapy that has not yet made its way into the veterinary field is the use of oncolytic viruses as a way to modulate the immune system.

Oncolytic viruses are genetically engineered tumor-killing factories that combine the specificity of mAbs with the ability to produce cytokines to direct and augment an immune response against the cancer. When an oncolytic virus is provided intratumorally, the resulting tumor necrosis creates an inflammatory response that alerts the immune system, leading to a systemic response against the cancer.

Currently, research is being conducted on genetically engineering polio, herpes, and adenoviruses. The only FDA-approved oncolytic virus in the human field is for advanced melanoma; Imlygic (talimogene laherparepvec — Amgen) is provided via intratumoral injection.

The creation of an oncolytic viral therapy that can be provided intratumorally and create a systemic anti-tumor response can be a viable opportunity within veterinary medicine.

Conclusion

While a faulty immune response can cause disease, the use of targeted immunotherapies allows for re-direction and regulation of the immune system. Balance is necessary in the immune systems of our companion animals, and many biopharmaceutical companies are working to bring more immunotherapies to market.

Providing safe, effective, and affordable immunotherapies to veterinary patients is an industry goal. There are many emerging therapies coming out of the human field and many emerging companies in the veterinary field working to address immune-mediated diseases in companion animals.

Can new immunotherapies commercialized in the veterinary industry lead to the next breakthrough and one day inform human research? I believe that with the support of the veterinary community, and the similarities between canine and human antigenic targets, we can.

Ashley Kalinauskas is the CEO of Torigen, a startup biotechnology company focused on providing personalized cancer immunotherapies to companion animals. Torigen is a team of veterinarians and researchers spun out of research from the University of Notre Dame focused on utilizing immunotherapy for cancer and immune-mediated diseases.

References

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2. Lu R-M, Hwang Y-C, Lee C-C, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27:1. doi: 10.1186/s12929-019-0592-z
3. Gedon NKY, Mueller RS. Atopic dermatitis in cats and dogs: a difficult disease for animals and owners. Clin Transl Allergy. 2018;8:41. doi: 10.1186/s13601-018-0228-5
4. Suckow MA. Cancer vaccines: harnessing the potential of anti-tumor immunity. Vet J. 2013;198(1):28-33. doi: 10.1016/j.tvjl.2013.06.005
5. Mahnke YD, Schwendemann J, Beckhove P, et al. Maintenance of long-term tumour-specific T-cell memory by residual dormant tumour cells. Immunology. 2005;115(3):325-336. doi: IMM2163 [pii].