Facilitating Immunotherapy Drug Development

Naiyer A. Rizvi, MD, an internationally recognized leader in the treatment of lung cancer and immunotherapy drug development, is Director of Thoracic Oncology and Immunotherapeutics in Medical Oncology at NewYork-Presbyterian/Columbia University College of Physicians and Surgeons. Dr. Rizvi’s research of antibodies that can reinvigorate T cells to recognize lung cancer cells as foreign and destroy the cancer cells has been a major development in thoracic oncology.

Dr. Rizvi has led key trials using immune checkpoint blockade therapy which unleash a patient’s own T cells to kill tumors, an approach that is revolutionizing cancer treatment. He continues this research with a focus on developing new immunotherapy agents and immunotherapy combinations to reshape the landscape of cancer therapy.

One of the latest immunotherapies to reach the market is a drug called nivolumab (Opdivo®), which the FDA recently approved for the treatment of patients with advanced squamous non-small cell lung cancer (NSCLC). “‘Groundbreaking’ and ‘revolutionary’ often overstate the case, but they truly apply to the impact of the new immunotherapy agents that target the PD-1 pathway for NSCLC by disabling the PD-1 protein on T cells and suppressing T cell activity,” says Dr. Rizvi.

Dr. Rizvi led the trial, published in the March 2015 issue of Lancet Oncology that was key to approval of nivolumab for squamous lung cancer. “When I first started treating patients with nivolumab in 2008, it was hard to imagine how dramatically this could help patients who were resistant to all of our standard treatments,” says Dr. Rizvi. “We have some patients who are still alive many years after taking this drug, with no evidence of cancer. This has never been seen with standard lung cancer treatment.”

While some patients with NSCLC respond well to PD-1 inhibitors, others do not. Dr. Rizvi and his colleagues thought that the cancers that had accumulated the most DNA damage were more likely to have worn out the immune system and would likely be helped the most by PD-1 inhibitors. They tested this by sequencing tumor DNA from both responders and non-responders to treatment with pembrolizumab (KEYTRUDA®), a PD-1 inhibitor. Among their findings, published in April 2015 in Science, was that patients with a great deal of DNA damage were far more responsive to treatment than those with less DNA damage.

“We were able to use advances in sequencing technology to study the entire exome – the protein-coding genes of the genome – of tumors from patients with NSCLC who were treated with pembrolizumab. We found that the more genetically damaged the tumor was, the more likely the patient was to respond to PD-1 inhibitors. This is an important first step toward being able to predict who will respond to PD-1 inhibitors and could be a new way to think about precision medicine based on the sequencing of tumor DNA,” says Dr. Rizvi. “This collaboration among clinical researchers, geneticists, and immunologists shows how a team of scientists can work together to help patients fight cancer.”

In October 2015, KEYTRUDA – following a multicenter trial of 280 patients with metastatic non-small cell lung cancer received accelerated FDA approval for the treatment patients whose tumors express PD-L1 with disease progression on or after platinum-containing chemotherapy.

Controlling Cancer Cell Growth with Radiotherapy and Immunotherapy

Silvia C. Formenti, MD, Radiation Oncologist-in-Chief at NewYork-Presbyterian/ Weill Cornell Medical Center and Chair, Department of Radiation Oncology at Weill Cornell Medicine, is an international expert in the use of radiation therapy for the treatment of cancer and a recognized leader in radiation oncology and breast cancer research.

Dr. Formenti’s groundbreaking work has transformed the paradigm in radiation biology, demonstrating the efficacy of combining radiotherapy with immunotherapy to control cancer cell growth in solid tumors. She has translated preclinical work into clinical trials in metastatic breast cancer, lung cancer, and melanoma, and has opened a new field of application for radiotherapy, whereby localized radiation can be used as an adjuvant to immunotherapy of solid tumors and lymphomas.

“Combining radiotherapy with immunotherapy is exquisitely interdisciplinary work, leveraging the most modern integration of pathology, imaging, surgery, medical oncology, and radiation oncology,” Dr. Formenti says. Under Dr. Formenti’s leadership, scientists in the Department of Radiation Oncology are conducting high-impact basic, clinical, and translational research, and in particular, radiobiological research, exploring the effects of ionizing radiation on tumor and normal tissue with findings translated into preclinical models that can lead to improved, personalized patient care.

Funded by the National Institutes of Health, the Department of Defense Breast Cancer Research program, and the Breast Cancer Research Foundation, Dr. Formenti has focused her research endeavors on personalized oncology – designing more effective, targeted treatments tailored to individual patients by combining radiotherapy with immunotherapy. Her laboratory discovered that this combination therapy overrides cancer’s ability to hijack the normal immune response that rejects tumor cells, creating a vaccine against the disease that is specific to each individual patient’s tumor. When applied to an experimental model of metastatic breast cancer, she found that this therapy was not only effective against primary tumors, but it also prevented the disease from spreading to the lungs by leveraging acquired immune memory. Dr. Formenti is investigating how this breakthrough, by tailoring the therapy to the specific molecular characteristics of individual tumors, can be rapidly adopted to treat patients suffering from various forms of metastatic cancer.

These and other novel approaches to better understanding and ultimately treating the complexities of cancer are underway, moving at an accelerated pace spurred on by enlightened programs in precision medicine and collaborations that cross multiple disciplines. Immunotherapy, alone or in combination with other therapeutic advances, are making their mark in clinical care. Several cancers that were once considered terminal are now treatable with targeted therapies.