Exploring Immunotherapy's Role in Osteosarcoma

Investigating pulmonary metastases instead of the primary tumor is the key to finding treatments for osteosarcoma, according to Nancy Gordon, M.D.

Gordon, a pediatric oncologist and research assistant at The University of Texas MD Anderson Cancer Center, believes immunotherapy could play a critical role in the treatment of patients with osteosarcoma and lung metastases, and her recent research has shown that targeting the PD-1/PD-L1 pathway can have therapeutic benefit in these patients.

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

Gordon recently spoke with CURE about her research, the next steps following the findings of the study, and what she envisions for the treatment landscape of osteosarcoma over the next decade.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 studies, 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 the 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 two 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 to see change in the treatment landscape of osteosarcoma in the next five 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.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 one, the pulmonary metastases is another one; 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.