Expert Anticipates Immunotherapy to Open Door to Novel Treatments in Osteosarcoma

Nancy Gordon, MD

According to Nancy Gordon, MD, immunotherapy stands to play a critical role in the treatment of patients with osteosarcoma and lung metastases. Her recent research has demonstrated that targeting the PD-1/PD-L1 pathway can show significant therapeutic benefits for these patients.

However, as she notes, not all patients with this disease can derive those benefits.

“The next steps will be to see what will be the best approach to create a clinical trial that will allow for pediatric patients to receive this therapy and see what the benefit will be, but it will have to be in patients with relapsed disease where there is only minimal disease,” she said.

OncLive: Can you give an overview of the osteosarcoma research you are involved in with targeting the PD-1/PD-L1 signaling pathway?

Gordon, a pediatric oncologist and research assistant at The University of Texas MD Anderson Cancer Center, sat down with OncLive to discuss this research and what she expects to see in the treatment landscape of osteosarcoma over the next decade.Gordon: In osteosarcoma, the main reason that patients die is because of pulmonary metastases. Immunotherapy for osteosarcomas has shown some benefit in different aspects. There has been treatment which has been delivered through cytokines, for example, interleukin-2 (IL-2). We have studies where we deliver IL-2 to the lungs, and the reason for it is we have shown that immune cells go to the tumors, but the problem is that they go and they leave. One of the ways you can help those cells stay within the tumor is by increasing their growth and proliferation; one of the ways you do it is by giving some of these cytokines, one of which is IL-2. We have studies and pre-clinical data that shows that it allows the immune cells to stay.

One of the problems with the immune cells is that they can express one of the checkpoints, which is PD-1 and PD-L1. What happens is that it restricts the ability of the cells to kill the tumors. We’re talking about all the immune cells—we’re talking about T cells, natural killer (NK) cells, and even macrophages.

In our studies¹, we showed that only by giving an antibody against anti—PD-1, you can actually have therapeutic benefit in osteosarcoma lung metastases. The tumors express PD-L1, but the fact that immune cells can express PD-1, that limited their ability to kill the tumor. By blocking the pathway, you activate those cells so they’re able to do their job.

What would you say are the next steps following the findings of that study?

We used a human osteosarcoma mouse model to generate the pre-clinical data that will be translated to the clinic. In that end, we showed in the model you can only see 2 types of immune cells—NK cells and macrophages. When we blocked the pathway, we saw that not only did these cells migrate to the tumor, but, particularly, we showed that the macrophages are the ones that probably contributed to the best therapeutic efficacy of this blocking agent.The next steps will be to actually translate it to the patients. There have been a few studies already in adults for all of these checkpoint inhibitors. One of the major things we had to take into account, particularly in children, is that it had to pass phase I studies in adults for us to be able to implement it in children.

Are there any noteworthy toxicities associated with targeting the pathways?

What would you like the community oncologists to ultimately take away from those findings?

What would you like to see change in the treatment landscape of osteosarcoma in the next 5 to 10 years?

Immunotherapy doesn’t work in the face of a big, bulky, huge disease. You have to have only minimal residual disease for immunotherapy to work. None of the agents in a lot of the tumors have worked on their own. There have been many studies looking at not only checkpoint inhibitors, but also in combination with chemotherapy and other agents. The next steps will be to see what will be the best approach to create a clinical trial that will allow for pediatric patients to receive this therapy and see what the benefit will be, but it will have to be in patients with relapsed disease where there is only minimal disease.In adults, there have been some patients that have shown very minimal signs of pneumonitis, because you can have some kind of cytokine release that can cause that. Some patients have shown fatigue, some patients have shown diarrhea, but really it’s brought more benefits to patients where therapy works, such as in melanoma and non—small cell lung cancer. That’s more benefit than anything else.First of all, that we have to take into account that not all solid tumors are the same; that these therapies might not work the same way in these tumors. Osteosarcoma, in particular, which is the tumor of my interest, is a very heterogeneous tumor, where there has been many difficulties in approaching the treatment of these tumors. No therapy has improved the survival of patients with osteosarcoma. Each patient has to be taken 1 at a time. Certain considerations have to be taken before you actually implement or enroll these patients, knowing what’s been done so that we don’t repeat the mistakes of previous studies.I think that we have to stop looking at the primary tumor. We have to mostly look at the pulmonary metastases. In a lot of the Patient-Derived Xenograft (PDX) models that have been developed, the genetics is 1, the pulmonary metastases is another 1; once you generate a different PDX from that metastasis, the genetics are different. Every cycle the genetics change, so immunotherapies in these cases might be very beneficial and will play a critical role for the treatment of these patients.

Reference

1. Dhupkar P M, Yu L, Gordon N, et al. Targeting the PD-1/PD-L1 Signaling Pathway for the Treatment of Osteosarcoma Lung Metastasis. Presented at: Connective Tissue Oncology Society Annual Meeting; Lisbon, Portugal; November 9-12, 2016. Paper 011.