Suzanne L. Topalian, MD, director, Melanoma Program, professor of Surgery and Oncology, Johns Hopkins Medicine, discusses the immunosuppressive microenvironment of nasopharyngeal cancer.

In an effort to find new combinations of immunotherapy for patients with nasopharyngeal cancer, investigators from Johns Hopkins Medicine analyzed the immunosuppressive tumor microenvironment. Topalian, a cancer immunologist, says that in order to do these sophisticated analyses of the microenvironment, multiple specialists need to work together. With the help of a pathologist, Topalian and her group of investigators were able to evaluate this area.

Topalian says that they found very robust expression of PD-L1, as well as PD-1, on the infiltrating T cells in the majority of nasopharyngeal cancer cases that were evaluated. Beyond that, LAG-3, IDO, and COX-2, were all identified in the microenvironment of these patients’ tumors. Topalian says that all these molecules can be targeted with drugs that are currently available in the clinic.

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Suzanne L. Topalian, MD, director, Melanoma Program, professor of Surgery and Oncology, Johns Hopkins Medicine, discusses the immunosuppressive microenvironment of nasopharyngeal cancer.
 

Dr. Topalian on the Immunosuppressive Tumor Microenvironment of Nasopharyngeal Cancer

Suzanne L. Topalian, MD, director, Melanoma Program, professor of Surgery and Oncology, Johns Hopkins Medicine, discusses the treatment of patients with nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is a very serious global health concern, explains Topalian. Only 70% of patients with early-stage disease will survive 5 years. The survival rate drops to less than 40% for those patients with metastatic stage IV disease. Topalian says that beyond the standard therapies of radiotherapy and chemotherapy, there is not much to offer patients with nasopharyngeal carcinoma.

Anti—PD-1 drugs are being developed in this space though, Topalian says. In the last year, there was a study on nivolumab (Opdivo) and a study on pembrolizumab (Keytruda), which both showed response rates of 20% to 25%. These results give a foundation to hopefully build upon, Topalian says. The tumor immune microenvironment is currently being studied extensively to find targets.

Dr. Topalian on the Treatment of Nasopharyngeal Carcinoma

Suzanne L. Topalian, MD, professor of Surgery, Johns Hopkins Medicine, discuses novel immunotherapy biomarkers in colorectal cancer (CRC).

Researchers are looking beyond PD-L1 expression as a biomarker for anti-PD-1 agents and instead considering how cancer genetics might play a role, says Topalian.

 It is possible that there are genetic markers in the tumor that can help identify patients likely to respond to PD-1 agents.

One example of this can be seen in MSI-high (MSI-H) in CRC, says Topalian. CRC patients with defects in DNA mismatch repair mechanisms often have a high-mutational burden.

The MSI test is one test that is commonly used to determine if patients have this mismatch repair detect. These patients are very likely to respond to anti-PD-1 therapy, probably because all of the mutations in their tumors create new proteins that can be recognized by a very risk immune response.

Dr. Suzanne L. Topalian on Immunotherapy Biomarkers in CRC

Suzanne L. Topalian, MD, professor of Surgery, Johns Hopkins Medicine, discusses the role of the PD-L1 biomarker and other biomarkers on the horizon for the use in immunotherapy.

PD-L1 is a difficult biomarker to use in every circumstance, says Topalian. It may be determined that it is useful in only some kinds of cancers, but not all, she adds. This is still a story that is evoloving.

There are additional biomarkers being investigated. This includes genetic biomarkers, says Topalian. Microsatellite instability (MSI) testing is one potenetial biomarker that has shown some success in colon cancer and other cancers. Patients that are MSI high have tumors that harbor many mutations and they are more likely to respond to PD-1 inhibitors, she says.

Another emerging is area is virus-associated cancers. About 20% of cancers are associated with a virus and these viruses are strongly seen by the immune system, says Topalian. Viruses in tumors could provide a biomarker of which patients are more likely to respond to anti-PD-1 therapy.

​Suzanne L. Topalian, MD, professor of Surgery, Johns Hopkins Medicine, discusses the role of the PD-L1 biomarker and other biomarkers on the horizon for the use in immunotherapy.

 Dr. Suzanne L. Topalian on PD-L1 and Emerging Biomarkers for Immunotherapy

Suzanne L. Topalian, MD, director, Melanoma Program, professor of Surgery, Johns Hopkins Medicine, discusses how the use of PD-1/PD-L1 inhibitors in multiple tumor types has dramatically evolved over the last 4 years.

The first report of a PD-1 antibody demonstrating clinical activity in 3 different cancer types was presented 4 years ago, Topalian explains. Though this was preliminary evidence, she admits, it was also very promising for the field. At the time, it was most surprising to see the responses in patients with non—small cell lung cancer.

In 2016, there are even more data being presented demonstrating the activity of anti—PD-1/PD-L1 agents in even more cancer types. Although researchers hoped that these outcomes would occur in the field, the responses seen across tumor types with these immunotherapy agents have exceeded expectations, she says.

Dr. Topalian on Evolution of PD-1/PD-L1 Agents in Oncology

Suzanne Topalian, MD, professor of surgery and oncology, John Hopkins Medicine, and director of the melanoma program, Sidney Kimmel Comprehensive Cancer Center,  compares biomarker detection for anti- PD-1 therapies like nivolumab to anti-CTLA-4 therapies like ipilimumab for the treatment of melanoma.

PD-1 and PD-L1 blocking drugs are more active at the tumor site, says Topalian. To determine markers for PD-1 drugs , investigators must look at the tumor itself and correlate them with clinical outcomes.  Anti-CTLA-4 therapies have a global impact on the immune response, so markers such as PD-L1 may not be relevant.  

Suzanne Topalian, MD, professor of surgery and oncology, John Hopkins Medicine, and director of the melanoma program, Sidney Kimmel Comprehensive Cancer Center, compares biomarker detection for anti- PD-1 therapies like nivolumab to anti-CTLA-4 therapies like ipilimumab for the treatment of melanoma.

Dr. Topalian on Biomarkers for Anti- PD-1 Therapies in Melanoma

Suzanne Topalian, MD, Professor of Surgery and Oncology at the Johns Hopkins University School of Medicine, discusses the possible implications of the preliminary data for the investigatory PD-1 targeted immunotherapy BMS-936558, which was presented at the 2012 ASCO Annual Meeting.

Topalian believes that the early-stage results are big news for immune therapy. The trial found that the agent was active in patients with advanced melanoma, renal cell carcinoma, and non-small cell lung cancer. However, the full spectrum of tumors this agent is effective against is not yet fully known and will require further investigation.

Although preliminary, the trial demonstrated the efficacy of inducing tumor regression through the reeducation of the immune system.

Dr. Suzanne Topalian, from the Johns Hopkins University School of Medicine, on the PD-1 Targeted Immunotherapy BMS-936558.

Dr. Topalian on the PD-1 Immunotherapy BMS-936558

Suzanne Topalian, MD, Professor of Surgery and Oncology at the Johns Hopkins University School of Medicine, discusses early-stage results of the targeted immune agent BMS-936558, a co-inhibitor of the programmed death-1 (PD-1) receptor that is expressed by activated T cells.

The phase I trial sought to discover if BMS-936558 was clinically active in pretreated patients with multiple tumor types, who, in some cases, had previously received three or more prior therapies.

Topalian notes that the most remarkable findings from the trial included patients with advanced melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC). Objective responses were 28% for patients with melanoma, 27% with RCC, and 18% for NSCLC.

The BMS-936558 trial is still ongoing and the results presented at the 2012 ASCO Annual Meeting were gathered at an interim analysis. However, according to Topalian, the preliminary data suggests that partial and complete tumor regression may last for longer than one year and disease stabilization may persist for more than six months, in some patients.

The trial plans to conduct an additional follow up at a later date, but early results have shown promising responses to BMS-936558 for patients with melanoma, RCC, and NSCLC.

Dr. Suzanne Topalian, from Johns Hopkins University School of Medicine, on the PD-1 Targeted Therapy BMS-936558

Suzanne L. Topalian, MD

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