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In the previous articles, we described how cancer immunotherapy may help dogs with aggressive cancer types including soft tissue sarcoma, hemangiosarcoma, and osteosarcoma.
But not every dog responds to immunotherapy treatment. Some dogs' tumors can actually develop resistance.
In this post, we'll review a new promising way to tackle this problem by combining multiple therapies to enhance the immune response and survival times.
Tumor Microenvironment (TME)
Cancer is a complex and dynamic disease. Cancerous tumor cells not only interact with the surrounding tissue and cells, but they also can develop multiple ways to evade the immune system, creating a protective environment around the tumor cells.
The tumor microenvironment (TME) is an ecosystem surrounding the cancer cells. consisting of heterogeneous cancer cells, immune cells, blood vessels, and various signaling molecules. The tumor microenvironment plays a critical role in tumor growth and metastasis.
In ideal situations, anti-cancer immune cells would be in abundance in the TME, especially "killer" T-cells that attack cancer cells. Instead, cancer cells attract different types of immunosuppressive cells which collectively shield the tumor from immune recognition and attack. These cells include:
Regulatory T cells (Tregs): These specialized immune cells suppress the activity of other immune cells, dampening the immune response against the tumor.
Myeloid-derived suppressor cells (MDSCs): MDSCs are a heterogeneous population of immature myeloid cells that can suppress immune responses. They inhibit the function of T cells and other immune cells, promoting tumor growth.
Tumor-associated macrophages and neutrophils: In different settings, macrophages and neutrophils are good cells protecting our bodies, but in TME, they help cancer progression with immunosuppressive properties.
But by combining therapies, it may be possible to target different aspects of the tumor microenvironment and overcome resistance, boost the immune response, help T-cells infiltrate the tumor, and increase the likelihood of lasting tumor control.
The challenge is to find the right combination that is effective, safe, and affordable.
The following are some examples of combination therapies already in use or which will soon be available.
Elias Cancer Immunotherapy
Elias Cancer Immunotherapy developed by Elias Animal Health Company in Olathe, Kansas, combines multiple immune-activating steps: vaccination with the patient's tumor sample, activated T-cell transfer, and IL-2 cytokine therapy. This combination approach has helped 40-50% of canine osteosarcoma patients in their small pilot study become long-term survivors.
Ruby is one of the lucky pups who was treated with Elias Cancer Immunotherapy at the University of Missouri. She was 8 years old when she was diagnosed with osteosarcoma. She tolerated the therapy well and was quickly back to running and chasing birds and rabbits. She was able to celebrate her 12th birthday, thanks to this combination therapy.
The therapy is today available only for dogs with osteosarcoma but in the near future, it may become available to treat sarcoma and other solid tumors in dogs. In fact, Elias's sister company is evaluating their approach in a clinical trial with human brain cancer patients.
TME Modifying Oral Drugs: Propranolol, Losartan, Toceranib
Did you know widely prescribed blood pressure medications (propranolol and losartan) can also modulate the immune system?
Researchers at Colorado State University and Tufts University led a series of studies demonstrating how inexpensive repurposed drugs (losartan and propranolol) plus another cancer drug called toceranib (aka Palladia) could block immunosuppressive cells and help TME become less cancer-friendly.
(By the way, these are oral drugs so, unlike chemo, they can be simply administered at home)
Giving patients just one of these drugs didn't make much difference. But a clinical benefit was seen in about 50% of patients with metastatic osteosarcoma who took high-dose losartan together with Toceranib - where the clinical benefit is defined as the sum of patients experiencing complete or partial response and stable disease. The study was small but has been one of the few studies showing promise for helping dogs with metastasis.
CSU researchers further experimented with the oral drug combination including propranolol - a common beta-blocker medication that also happens to have multiple anti-cancer properties. They studied
Propranolol + Losartan + Toceranib - for dogs with metastatic osteosarcoma
Propranolol + Losartan + Cancer Stem Cell Vaccine - for dogs with a brain tumor (glioma)
Propranolol + Losartan + Radiation Therapy - for dogs with sino-nasal carcinoma
The results were not perfect but they observed more T-cells infiltrating the tumors and concluded these oral drugs could enhance the efficacy of cancer vaccines and radiation therapy as well.
After Scout was diagnosed with osteosarcoma, he received amputation and chemo, but his cancer metastasized to his lungs. After enrolling in CSU's trial, Scout began taking propranolol, losartan, and toceranib at home. A few months later, his lungs became clear of tumors, and he is back hiking in the mountains of Colorado. (Source: CSU and U of Colorado)
Could adding propranol, losartan and/or toceranib enhance the efficacy of Elias immunotherapy? How about combining them with EGFR/HER2 vaccine, Immunocidin, or Torigen vaccine?
These questions remain to be answered with the help of future studies.
By the way, dogs with hemangiosarcoma may live longer when propranolol is added to chemotherapy. U of Minnesota researchers are investigating this treatment but some oncologists are proactively adopting this approach.
Checkpoint Inhibitor Combination Therapies
Cancer Checkpoint Inhibitor drugs have revolutionized human cancer treatment, making some incurable cancers treatable.
These medications work by blocking the signals that cancer cells use to inactivate cancer-killing T-cells.
By adding a second synergistic checkpoint inhibitor drug or another type of immunotherapy, scientists are discovering that the treatment efficacy can be boosted so that many more patients become survivors
For example, Paul a 67-year-old retiree who lives in Fort Worth Texas was diagnosed with Stage 3 melanoma and had his tumor surgically removed. The cancer recurred 18 months later. Luckily, he was able to enroll in a trial that combined an FDA approved PD-1 checkpoint inhibitor drug with another newer immunotherapy drug that targets LAG3 Three years later, he remains cancer-free. According to MD Anderson Cancer Center report, "Paul was among the 57% of patients in the trial who experienced a pathologic complete response." Canine versions of checkpoint inhibitor drugs are only available in a small number of clinical trials. A PD-1 checkpoint inhibitor developed by Merck called Gilvetmab is expected to become available later this year. Several other companies including Biotesserae (Oregon State University spinout) and Vetigenics (U of Penn spinout) are working hard to ensure dogs can benefit from the checkpoint inhibitor therapies.
The hope is that the new checkpoint inhibitor drugs will help enhance survival in more dogs, especially in combination with cancer vaccines and other immunotherapy treatments.
CCA is supporting several combination immunotherapy studies including those combining checkpoint inhibitor drugs. These studies are not possible without the support of our big-hearted donors whose gifts make research happen. To donate to CCA's research fund, Unleashing Hope, please visit this page.
In the next article, we'll cover the impact of fasting and other dietary interventions on cancer treatments.
Questions? Email us at info@ccralliance and we'll get back to you as soon as we can!
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All information provided by the Canine Cancer Alliance website is for informational purposes only. It is not intended to be a substitute for professional veterinary advice.
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