September 7, 2022
Even heroes need partners. As researchers are discovering, immunotherapy — the avatar of a new approach to cancer treatment — often works better when paired with other types of therapy.
Some 5,000 clinical trials are currently under way in the United States combining immunotherapy and other treatments. And several such combinations have already become standard treatment for certain cancers, including a chemotherapy/immunotherapy regimen for some patients with non-small cell lung cancer.
That amount of clinical testing — and formal approvals of a still-novel approach to treatment — doesn't happen unless the approach is thought to have exceptional potential.
Expectations for this "plus" approach to immunotherapy are high because of what immunotherapies have accomplished on their own. For some cancers, immune-based therapies like checkpoint inhibitors and CAR T-cell therapies have redrawn the boundaries of what treatment can accomplish. In metastatic melanoma, a disease for which there were no approved treatments 15 years ago, immune checkpoint inhibitors consistently produce long-lasting remissions, and often cures, in more than 25% of patients. CAR T-cell therapies have produced full remissions in 90% of patients with acute lymphoblastic leukemia and up to 70% of those with chronic lymphocytic leukemia or non-Hodgkin lymphoma.
Results like those deserve to be extended. For although immunotherapy has worked magnificently for some patients with some cancers, its overall track record has been uneven. Some malignancies, such as pancreatic cancer, prostate cancer, and glioblastoma, have been largely resistant to single-agent immunotherapies. And even in some cancers where immunotherapy has scored its biggest successes, not all patients benefit (although those that do benefit often have thorough, long-lasting remissions).
Around the world, scientists are working to broaden immunotherapy's range and reach — to enhance its effectiveness in cancers where it has already been successful, empower it against more types of cancer, and lengthen the remissions it triggers. This may involve developing new types of immunotherapies or upgrading ones already in use. Most often, however, it will involve pairing immunotherapy with other treatments.
"When you have therapies that individually can be effective against cancer, it makes sense to study whether combining them provides even greater benefits," says F. Stephen Hodi Jr., MD, director of Dana-Farber's Center for Immuno-Oncology, a hub of immunotherapy research at the Institute. "We're seeing multiple examples of therapies that can enhance the activity of immunotherapies with generally manageable side effects."
Clinical trials of such combinations are producing encouraging results, but the full potential of this approach probably won't be apparent for years. The number of ways immunotherapy can be combined with other agents is immense, and the task of determining which combinations work best for which patients under what conditions will take substantial amounts of time — and, likely, thousands more trials — to sort out. As is often the case in science, instances where particular combinations prove ineffective are apt to be as informative as those where combinations are successful.
An Army of Specialists
Cancer immunotherapy is a general term for treatments that harness the immune system to fight malignancies. The range of such treatments is broad because the immune system itself is diverse. Consisting of macrophages, monocytes, B cells, T cells, natural killer cells, myeloid cells, and other cell types, regulatory substances like chemokines and cytokines — as well as antigens, antibodies, and other components, each with their own roles and responsibilities — the immune system is a marvel of specialization. It is also highly dynamic, in constant touch with the rest of the body, mustering an attack on an invader or diseased cell when necessary, drawing back when the battle is over. Most immunotherapies target one or another of these elements, seeking to tweak the immune response to better target cancer.
The complexity of the immune system is one of its greatest assets in fighting disease — and poses one of the greatest challenges to researchers developing and studying immunotherapies. The variety of cells, proteins, and chemicals that make up the immune system represent countless targets for new drugs and other therapies. At the same time, the many moving parts of the system make it unlikely that any one immunotherapy agent could marshal the full force of the immune system's capabilities against cancer.
"The immune system presents a wealth of opportunities for treating cancer," says Patrick Ott, MD, PhD, director of clinical sciences at the Center for Immuno-Oncology. "Immune system cells, proteins, and signaling molecules all could potentially be modulated to strengthen the immune response. Finding combinations that can work within this complexity is a challenge – that's the focus of the field today."
Testing the Environment
Clues to single-agent immunotherapy's effectiveness in some cancers — and its less impressive results in others — can be found in a tumor's "immune microenvironment." Physicians and scientists traditionally thought of cancer in terms of the tumor cells that grow within a tissue, and traditional approaches to therapy — surgery, radiation therapy, chemotherapy, and targeted therapy — specifically targeted those cells.
But view a tumor sample under a microscope and it's clear there's more to cancer than tumor cells. Mixed in with the malignant cells in many tumors is an assortment of normal cells, blood cells, blood vessels, and immune system cells of various types and temperaments. Some of these immune cells are apt to be on the attack; others may simply be loitering. Still others may actually be reining in the immune attack.
From the standpoint of immunotherapy, each of these "ancillary" aspects of a tumor represents a potential ally in battling cancer. Immunotherapy agents aim to alter the immune microenvironment in ways that will rally its forces more effectively against tumors.
Current immunotherapies take a variety of approaches to this goal. Immune checkpoint inhibitors cause tumor cells to lower their guard against cancer-fighting T cells. Cancer vaccines use cells or parts of cells to spur an immune attack on cancer. CAR T cells are engineered to latch onto and destroy tumor cells. Monoclonal antibodies are lab-made versions of natural proteins that zero in on specific parts of cancer cells.
Even as they engage elements of the immune system, single-agent immunotherapies can't always rouse a sufficient response to cancer. A treatment that lowers the barriers to a T cell attack, for example, won't be successful if there aren't any T cells in the vicinity of a tumor. A therapy that stimulates T cells may have the unwanted effect of activating T cells whose job is to suppress an immune attack. Some cancers excel at not calling attention to themselves, essentially flying below the immune system's radar. Others mutate so they're able to jam the immune system's signaling circuits.
Combining immunotherapy with other types of treatment offers a way to overcome these obstacles. The history of cancer treatment offers ample evidence that two (or more) therapies can often accomplish what one alone cannot.
Some combinations rely on the power of addition: One treatment takes aim at a particular weakness of cancer cells, while its companion treatment targets another. Others — which are thought to hold the greatest potential — work synergistically, one therapy making the tumor more vulnerable to attack by the other.
Dana-Farber researchers are designing, leading, and participating in dozens of trials of immunotherapy in tandem with other treatments. Many of these trials are newly opened, some are well under way, some are closed and their data being analyzed, and some are in the planning stages. Together they offer a mosaic of the variety of combinations being studied and an early inkling of their effectiveness.
Here is a sampling of such trials at Dana-Farber, illustrating the range of approaches currently being explored.
Immunotherapy Plus Chemotherapy
It was initially thought that chemotherapy and immunotherapy would make a good couple because the killing of tumor cells by chemotherapy can lead to the exposure of substances called neoantigens. The disclosure of these structures, which arise from mutations and other changes within cancer cells, can spark an immune attack on the cells. Research has shown that other, more powerful, mechanisms are also at work.
Leena Gandhi, MD, PhD, director of Dana-Farber's Center for Cancer Therapeutic Innovation, explains: "Many chemotherapies cause tumor cells to lyse, or disintegrate, which exposes neoantigens [which can be recognized as 'foreign' by the immune system]. The immune system responds by expanding the population of T cells that recognize those antigens. Some chemotherapy agents can also trigger an increase in inflammatory factors and other stress-induced changes in the tumor microenvironment during cell killing, which cause T cells to proliferate and become active against cancer."
Gandhi led a pivotal phase 3 clinical trial of chemotherapy and pembrolizumab — a checkpoint inhibitor targeting the PD-L1 protein on tumor cells — in patients with non-small cell lung cancer, the most common form of lung cancer. Prior to the trial, pembrolizumab was generally reserved for patients whose tumors were high in PD-L1. The trial showed, however, that the combination significantly improved survival in all patients, regardless of whether their tumors tested positive for PD-L1. "That really changed the standard of care for this form of lung cancer," Gandhi states, "and became the gateway for many other chemotherapy combinations in many other kinds of cancers."