Nivolumab + stereotactic radiosurgery
A new clinical trial has opened for chordoma patients with advanced or metastatic tumors testing a cancer immunotherapy drug called nivolumab in combination with stereotactic radiosurgery (SRS). The goal of these therapies is to harness the body’s own immune system to more effectively fight chordoma.
Dr. Michael Lim is the Principal Investigator for this research study at Johns Hopkins Hospital, and Dr. Josh Yamada is the Principal Investigator at Memorial Sloan Kettering Cancer Center (MSKCC) – two centers that are leaders in chordoma treatment and research. Enrollment is currently open at Johns Hopkins and will open at Memorial Sloan Kettering in the coming months.
The Chordoma Foundation is proud to support this clinical trial with a $300,000 research grant, made possible by the contributions of many in the chordoma community. It represents the culmination of research the Foundation has supported in Dr. Lim’s lab since 2011. We are grateful to everyone whose generosity and persistence over that time has helped bring this trial to fruition.
Rationale for the trial
As the body’s primary defense mechanism against disease, part of the job of the immune system is to find and destroy diseased cells, including cancer cells. However, cancer cells often find ways to avoid being killed by the immune system, and when this happens a tumor can grow unchecked.
There are several ways cancers cells can escape attack by the immune system. One common way is by producing proteins called “immune checkpoint” molecules, which deactivate the immune system’s cancer-killing T cells. On normal, healthy cells, immune checkpoint molecules protect them from being attacked by T cells. However, scientists now know that many cancers produce these checkpoint molecules, which act as brakes on the immune system. One checkpoint molecule that cancers commonly display is called PD-L1, which shuts down T cells by binding to a receptor called PD-1 on the T cell.
This knowledge has recently led to the development of drugs that block the interaction of PD-1 and PD-L1, thereby preventing cancer cells from dodging attack by T cells. Nivolumab is one example of this type of drug called a checkpoint inhibitor. Such immune checkpoint inhibitors are already approved to treat certain types of cancers, including melanoma, lung, kidney, and bladder, but their impact on chordoma remains to be determined. (See here for a description of how checkpoint inhibitors work.)
In a 2015 paper in the Journal of Neuro-oncology, Dr. Lim and colleagues at Johns Hopkins University showed the first evidence that chordomas use checkpoint molecules, including PD-L1, to avoid immune attack. Since then, several other research groups have independently published similar results, providing strong rationale to explore checkpoint inhibitors as a strategy for treating chordoma.
However, enabling the immune system to kill chordoma cells may require more than just a checkpoint inhibitor.
Even if a checkpoint inhibitor can release the brakes that cancer puts on the immune system, sometimes cancer cells don’t appear abnormal enough to the immune system to trigger a response. One potential way to overcome this challenge and make cancer cells more visible to the immune system is with stereotactic radiosurgery (SRS) – a high dose of focused radiation that is delivered to the tumor over a small number of sessions. SRS is already a standard treatment that is used to help control advanced or metastatic chordoma tumors (it is sometimes called CyberKnife or Gamma Knife, which are the names of machines used to deliver the radiation).
SRS is thought to be able to stimulate a heightened immune response by causing tumor cells to burst, exposing their abnormal contents to the immune system. It also may make tumor cells more sensitive to being killed by the immune system.
This understanding has provided rationale for testing the combination of checkpoint inhibitors with SRS. Preliminary results from clinical trials testing this combination in other tumor types have shown evidence of enhanced antitumor activity compared with SRS or a checkpoint inhibitor alone. More recently, Dr. Lim and colleagues at Johns Hopkins University showed that this combination reduces tumor growth and improves survival in a mouse model of chordoma.
Based on this evidence, the Chordoma Foundation’s Medical and Scientific Advisory Boards endorsed the concept of a clinical trial testing the PD-1 inhibitor nivolumab alone and in combination with SRS.
About this trial
This research study is designed specifically for chordoma patients 15 years or older with recurrent, advanced or metastatic tumors. The primary goal of this study is to determine the safety of nivolumab alone or in combination with SRS for treating chordoma. The secondary goal is to determine whether these therapies can shrink or stop the growth of chordoma tumors.
Patients in this research study will be assigned to one of two treatment groups. Patients assigned to the first treatment group will receive nivolumab alone at the same dose that is commonly given to patients with other tumor types. If any harmful side effects are seen, the dose will be reduced until a safe dose is found for chordoma patients. Patients assigned to the second group will receive nivolumab plus treatment with SRS. If patients have already had radiation they may or may not be able to receive SRS, depending on the location and dose of the prior radiation and the location of the current tumor.
All treatments will be given at Johns Hopkins Hospital in Baltimore, MD or at Memorial Sloan Kettering in New York City, NY, so study participants must be willing and able to travel to the site at which they enrolled for the duration of the study. Nivolumab will be provided to participants at no cost. Patients will be able to stay on nivolumab for up to 2 years or until their tumor grows or they experience intolerable side effects.
Potential impact
This trial represents the first time that an immune checkpoint inhibitor will be tested for the treatment of chordoma. As such, it is expected to provide many lessons that could inform future treatment and research.
At the most basic level, this trial will establish whether chordoma patients can tolerate the same dose of nivolumab that is used to treat other tumor types, and whether nivolumab can be given safely in combination with SRS.
If patients respond on the trial, that would provide strong rationale to further explore checkpoint inhibitors alone or in combination with SRS as a treatment strategy for chordoma. It may also provide the justification needed for insurance companies to cover the off-label use of nivolumab for the treatment of chordoma. Regardless of the outcome, the trial investigators will be able to study why patients do or do not respond, which could provide crucial insights into how chordoma interacts with the immune system and inform the use of other types of immunotherapy for chordoma.