A promising potential treatment for osteosarcoma

Alejandro Hernandez / stock.adobe.com

Osteosarcoma

Cancer is the leading cause of death in dogs over the age of 10.¹ Of those cancers, osteosarcoma is the most common primary bone tumor found in dogs.² In most cases, it occurs in middle-aged to older, large, and giant breed dogs. It is estimated that approximately 10,000 dogs per year in the United States are diagnosed with this aggressive and generally fatal disease.³

Although the exact cause of osteosarcoma is unknown, strong genetic predispositions are evident. The tumor causes lameness, swelling, and pain in the affected bone, and it weakens the bone structure, making it likely to fracture spontaneously. The tumor most commonly spreads to the lungs but may also spread to other tissues, including other bones and internal organs.

Osteosarcoma also occurs in humans and most commonly affects children in their first or second decade of life; however, the annual incidence is lower than in dogs, affecting approximately 400 children per year in the United States.⁴ The disease in pediatric patients shares similar clinical, biological, and molecular features to dogs, including shared genetic mutations and a chaotic chromosomal genetic pattern that is typical of the tumor. Clinically, the tumor tends to occur more commonly in the growth plate regions of the long bones (ie, appendicular skeleton) compared with the axial skeleton (ie, skull, spine, pelvis).

Standard-of-care treatment for osteosarcoma consists of a combination of surgery to remove the tumor either through amputation or limb-sparing surgery and chemotherapy, aimed at controlling tumor cells that may have already spread to other parts of the body. In some instances, where definitive surgery to remove the tumor is not possible, radiation is employed to control bone pain (palliative radiation) or provide local tumor control (stereotactic radiation). Despite these treatments, some cancer cells usually survive, leading to disease relapse and progression. Unfortunately, 85% to 90% of dogs with osteosarcoma will die from relapsed, drug-resistant metastatic disease, and median survival time post diagnosis is approximately 320 days.⁵

Innovative cancer treatment: Immunotherapy

Nicola J. Mason, BVetMed, PhD, DACVIM, MRCVS, is a professor of medicine and pathobiology at the University of Pennsylvania School of Veterinary Medicine (Penn Vet) in Philadelphia. In 2012, Mason advanced a new approach aimed at stimulating the patient’s immune system to “wake up” and recognize osteosarcoma tumor cells in the body and eliminate them. This approach falls under the general umbrella of treatments known as immunotherapy and was administered after standard-of-care amputation and chemotherapy. Immunotherapy describes an ever-increasing array of therapeutics that serves to initiate and augment antitumor immune responses that specifically kill cancer cells and provide long-lasting clinical effects.

Various immunotherapeutic approaches have been responsible for some remarkable durable clinical outcomes in human patients with either blood cancers or solid tumors. However, there is still much to learn about how best to use immunotherapy and how to predict which patients will most likely to respond to it. Many of the answers to these questions can only come from clinical trials with patients who have spontaneously developed cancer. These include pet dogs who desperately need new treatments that are safe and more effective than the current standard of care. Given that dogs naturally develop tumors that are very similar to those that occur in humans, pet dogs with cancer are being increasingly recognized as a relevant parallel patient population in which to study new treatments. To this end, the National Cancer Institute is spending more than $20 million to perform comparative immunotherapy clinical trials in dogs with cancer to inform the use of these novel therapies in human patients while also helping the dogs.

“We felt that there was a need to try to improve the outcomes of dogs with osteosarcoma, and that a similar approach might also improve the outcomes of pediatric patients with this disease. We hoped that by using an immunotherapeutic approach, we could educate the dog’s immune system to recognize and kill tumor cells remaining in the body after standard-of-care amputation and chemotherapy, delay or prevent metastatic disease, and prolong survival. We also hoped the immunotherapy would be well tolerated and not have any adverse effects on our patients,” Mason said.

“The chemotherapy drug, carboplatin, is used for dogs with osteosarcoma and is fairly well tolerated,” Mason continued. “[However], children are treated with a much more intensive chemotherapy regimen, and although their clinical outcomes are better compared [with] dogs, [approximately 70% of human patients that present with osteosarcoma that has not metastasized will respond to that therapy and will not experience disease relapse]. They tend to experience long-term health issues associated with the chemotherapy they received as children. Commonly experienced, long-term adverse effects of chemotherapy include infertility, cardiomyopathy, and secondary cancers. Furthermore, children who present with metastatic disease have a worse prognosis, and their 5-year survival rate is as low as 20%.”

There is a real need to help children with osteosarcoma and provide safer and more effective therapies for them, and the same need is seen for dogs with this disease. Because the disease is very similar in dogs and children, if there is an approach that is found to be effective in canines, there is hope that it will also be effective in children.

Mason’s immmunotherapeutic approach to treat osteosarcoma involves using a highly weakened form of the bacteria Listeria monocytogenes (L monocytogenes), whichis a potent stimulator of the innate and adaptive arms of the immune system. The general concept of using bacteria to stimulate immune responses against cancer goes back to the late 1800s, but now with the capabilities of genetic engineering, the bacteria can be modified to express tumor-associated molecules, such as HER2/neu, which is often expressed in canine and pediatric osteosarcoma and in other cancer types such as breast cancer. When the modified L monocytogenesis administered to the patient, it fools the immune system into believing that any cell that expresses the HER2/neu molecule is infected with L monocytogenes, and therefore the immune system is trained to kill those cells. Those cells are the tumor cells, and the immunotherapy has educated the immune system to look for HER2/neu-expressing cells and kill them.

“Basically, we use the modified [L monocytogenes]as a ‘Trojan horse’ to take the HER2/neu molecule into the body and present it to the immune system, directing potent immune responses against the osteosarcoma tumor cells and hopefully eliminating them from the body and preventing disease relapse,” Mason said.

Golden retriever: Sandy

The story of Sandy the golden retriever is sadly a relatively common one. When she developed lameness in her front leg, her owner thought she might have sprained it while actively exercising and jumping. At the veterinarian, she was treated with anti-inflammatories and showed some improvement, but this was short-lived. The lameness returned, and radiographs of her leg at that time showed a typical osteosarcoma lesion in her front leg. The prognosis was bleak, even with standard-of-care amputation and 4 doses of carboplatin chemotherapy. Sandy’s disease was expected to resurface in her lungs and most likely cause her death within 1 year.

“After her diagnosis of osteosarcoma, Sandy came to Penn Vet in 2018 to take part in a clinical trial to evaluate whether the HER2-expressing [L monocytogenes] could be safely used to prevent metastatic disease after standard-of-care amputation and chemotherapy. Sandy did very well after her amputation and chemotherapy and had no evidence of disease spread at the time she started receiving the [L monocytogenes]treatment.” Mason’s team was hoping to stimulate Sandy’s immune system against any remaining tumor cells in her body. If the immune system could find these cells and kill all of them, then perhaps Sandy would not develop metastatic disease and would survive.

Sandy received 3 doses of the L monocytogenesvaccine. Within several hours of each dose, Sandy began to feel unwell and developed a mild fever. She was given intravenous fluids, which brought her temperature down, and she was able to go home after eating her dinner on the same day. The same response to the L monocytogenesvaccine occurred each time Sandy received it. She also received antibiotics for 3 days after treatment to ensure there were no remaining L monocytogenesin the body. In the absence of any gross tumor, it seems that the patients can kill off the L monocytogenesvery effectively, so the antibiotics are used only as a precaution. Sandy underwent amputation and L monocytogenesimmunotherapy 4 years ago and is doing well and appears to be cancer free at this time.

“We are delighted for Sandy and her owner. When the median survival time for this disease is [approximately] 10 months with standard-of-care treatment, any patient who survives 4 years is doing very well indeed. Not all dogs have experienced the same increase in survival, however, and it is now very important to understand why some dogs like Sandy appear to respond very well, [whereas] others do not. Once we understand this, we hope we might be able to turn nonresponders into responders or provide alternative approaches that might be more effective for those predicted nonresponders,” Mason said.

“We are trying to find a better way to determine which are the best treatments to take forward from the dogs into humans with osteosarcoma,” Mason said. Because the results from the firstL monocytogenesclinical trial in pet dogs were encouraging and showed that the dogs tolerated the immunotherapy very well, and that survival time was significantly increased, they were submitted to the FDA. The FDA then approved the start of a phase 1 clinical trial using the same modified L monocytogenesto treat children and young adults with relapsed osteosarcoma.

Mason is 1 of several veterinary clinician scientists working to bring novel immunotherapy approaches into the clinic to treat dogs—and hopefully humans—with osteosarcoma. Similar types of ongoing clinical trials for dogs with osteosarcoma and other tumor types can be found at precinctnetwork.org.

References

1. Davis BW, Ostrander EA. Domestic dogs and cancer research: a breed-based genomics approach. ILAR J. 2014;55(1):59-68. doi:10.1093/ilar/ilu017
2. Szewczyk M, Lechowski R, Zabielska K. What do we know about canine osteosarcoma treatment? Review. Vet Res Commun. 2015;39(1):61-67. doi:10.1007/s11259-014-9623-0
3. Bone cancer in dogs. American Kennel Club Canine Health Foundation. May 20, 2010. Accessed May 3, 2023. https://www.akcchf.org/canine-health/your-dogs-health/bone-cancer-in-dogs.html
4. Osteosarcoma. St Jude Children’s Research Hospital. Accessed May 3, 2023. https://www.stjude.org/disease/osteosarcoma.html
5. Kent MS, Strom A, London CA, Seguin B. Alternating carboplatin and doxorubicin as adjunctive chemotherapy to amputation or limb-sparing surgery in the treatment of appendicular osteosarcoma in dogs. J Vet Intern Med. 2004;18(4):540-544. doi:10.1892/0891-6640(2004)18<540:acadaa>2.0.co;2