James Researchers Look to Build on Immunotherapy Breakthroughs

Cancer Research  OSUCCC  James

The human body’s immune system has evolved over millions of years into a highly effective destroyer of foreign invaders.

“The immune system allows us to survive in an environment filled with all sorts of bacteria and viruses,” said David Carbone, MD, PhD, Director, James Thoracic Center of The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James). “If you didn’t have an immune system, people would die at a very young age from infections.”

The immune system’s main weapons against cancerous cells are T-cells, Natural killer (NK) cells and macrophages. They locate and attack these foreign invaders.

“They have to know what is self and what is not self, and when their response is effective and when to turn it off,” Dr. Carbone said.

Cancer cells are also capable of evolving to evade the body’s immune system. And when they do, these fast-growing cells form rapidly growing tumors that metastasize and spread throughout the body.

“Cancer cells develop all the time and the body’s immune system eliminates them,” Dr. Carbone said. However, some cancer cells are able to produce a “force field” around these growing clusters of mutant cells. “And suddenly that cancer cell is protected from T-cell attack and grows and becomes a tumor.”

In recent years, doctors and scientists such as Dr. Carbone and his colleagues at the OSUCCC – James and at cancer centers around the world, have developed ways to re-energize the body’s immune system, overcome these “force fields” surrounding cancer cells and enable the immune system to seek out and destroy these rogue cells.

This is called immunotherapy, and it is one of the most promising areas of cancer research and treatment. Several immunotherapy drugs have been approved by the U.S. Food and Drug Administration (FDA), and many more are currently in clinical trials at the OSUCCC – James and other cancer centers and are showing great promise.

Dr. Carbone, who came to the OSUCCC – James in 2012, has been at the forefront of this exciting new area of research and treatment since the 1990s.

Most lung cancer patients aren’t diagnosed until their disease was in the late stages and had already spread to other parts of the body. When Dr. Carbone completed his joint MD/PhD program in 1985, “there were very few active therapies for lung cancer patients,” Dr. Carbone said. “There was some chemotherapy available, but back then it wasn’t even offered to most lung cancer patients because the survival prolongation was so short, and the side-effects often severe.”

By the mid 1990s, advances in reading and understanding the genetic code of the cancer cells led Dr. Carbone to recognize that lung cancer wasn’t caused by one genetic mutation, but by scores of mutations. And it sparked an idea.

“I came up with the idea of targeting the mutations that were features of the lung cancer cells that make them different from normal cells,” Dr. Carbone said. “We did research to see to see if the T-cells could recognize these mutated-protein products on the cancer cells.”

The answer was yes, “and we published some of the first papers in the early 1990s that showed T-cells could recognize mutated patterns in cancer cells and kill them and not kill the normal cells,” Dr. Carbone said.

Think of cancer research as completing a very complicated puzzle, with pieces contributed by many different people. The basic science work of Dr. Carbone and his lab was one piece, but the discovery by others of another key piece of the puzzle, PD-L1, started to make the picture complete.

“It was found that an important immunologic checkpoint protein was PD-L1,” Dr. Carbone said. “It acts like a force field around the cancer cell. If you have a drug that blocks PD-L1, a checkpoint inhibitor, it allows the immune system to see and kill the cancer.”

Examples of PD-L1 checkpoint inhibitor drugs approved to treat lung cancer are: Nivolumab, Pembrolizumab and Atezolizumab.

These drugs have improved Dr. Carbone’s ability to treat and prolong the lives of his lung cancer patients, especially those whose tumors have a high expression of PD-L1. This is about 25 to 30 percent of his patients. “The response is 45 to 50 percent in the patients with the highest PD-L1 markers, which means major shrinkage or total elimination of the tumors,” he said. “We’re now five or seven years out and in a small percentage of people, 5 to 10 percent, their cancer has not come back.”

These gains are just the beginning of immunotherapy, which Dr. Carbone said is still in the early stages of development.

“We are just learning how to best use these drugs and combine them with standard therapies. In addition, the hope is that PD-L1 is the first of many targets for immune therapy treatment,” he said, adding his lab is looking at other markers that could predict immunotherapy efficacy in addition to high expression of PD-L1, such as the tumor mutation burden (TMB). “In patients that have both high PD-L1 and high TMB, there are indications that immunotherapy will lead to even better outcomes,” he said, adding other clinical trials are trying to determine if chemotherapy and immunotherapy together lead to better outcomes than each individually.

The FDA recently approved the first gene therapy, immunotherapy treatment (Yescarta) for adult patients with certain types of large B-cell lymphoma who have not responded to previous treatments and/or relapsed. In this treatment, a patient’s T-cells are collected and sent to a lab, where they are genetically modified to better attack and kill lymphoma cells, and then infused back into the patient. This process is known as chimeric antigen receptor (CAR) T-cell treatment and the OSUCCC – James is one of the few cancer centers currently approved to offer Yescarta to patients.

“Building on these results, we are looking at new therapies for lung cancers involving gene-modified T-cells,” Dr. Carbone said, adding the OSUCCC – James is involved in other clinical trials for CAR T-cell treatments.

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D.

All these breakthroughs are what fuels Dr. Carbone. He’s determined to learn how to increase the response rate to immunotherapy in his patients. “Why don’t 50 percent of our patients respond, and why do some have long responses and some have short responses?” he asked, determined to find the answer.

The answers to these and so many other questions are being answered.

“There are thousands of clinical trials going on for immunotherapy and new results are coming out every month,” Dr. Carbone said. “This is a very exciting time. It may turn out that PD-L1 is the only good target, but I think we’ll find other targets for immunotherapy. And, being part of this process, with patients and in the lab, is what makes this position at The James very satisfying for me.”