Cancer Immunotherapy: Fighting Cancer From Within

The U.S. Food & Drug Administration has approved immunotherapies for some two dozen cancer types – from successful CAR T-cell therapy for acute lymphoblastic leukemia, to PD-1 checkpoint inhibitors for melanoma and non-small cell lung cancer, to therapeutic vaccines for pancreatic cancer. Thousands of clinical trials currently underway hold promise for more progress to come.

With its focus on funding transformational research in new drug development and finding novel uses for existing therapies, Gateway for Cancer Research is at the vanguard of this promising field of cancer research.

What is cancer immunotherapy?

Simply put, cancer immunotherapy enlists the power of the human immune system to fight cancer, either by stimulating its natural function, or by introducing targeted biological therapies that help restore or strengthen it. It is a starkly different approach – instead of targeting cancer cells themselves, newer immunotherapies activate immune cells in and around cancers.

The human immune system is a formidable weapon against infection and disease. Leukocytes, or white blood cells, patrol the body searching for and destroying disease-causing microbes and providing general immune protection. They seek out the proteins, or antigens, that all living cells – including cancer cells – express on their surfaces. The immune system recognizes antigens on normal cells as “self” and passes them by. Antigens on microbes or abnormal cells are detected as “foreign” and trigger an attack. Specialized immune cells called killer T-cells target cancer cells and prompt them to self-destruct.

The immune system does, indeed, help to prevent and slow the development of cancer. However, cancer cells develop mechanisms for undermining and evading it.

Unlike bacteria and viruses that are easily recognizable as “foreign”, cancer originates in our own cells, where it can masquerade as “self.” Cancer cells can undergo genetic changes that reduce their expression of tumor antigens making them less detectable. They have surface proteins that inactivate immune cells. And they can recruit normal cells around the tumor to help suppress immune response.

Types of Cancer Immunotherapy

T-cells have “brakes” on their surface called immune checkpoint proteins. When these proteins recognize specific proteins on other cells, an “off” signal tells the T-cell not to mount an immune response.

One widely studied immune checkpoint protein, PD-1, controls apoptosis, the “programmed cell death” that is part of normal development. Certain cancer cells express high levels of its partner protein, PD-L1, which turns the T-cells “off”, enabling the cancer cell to evade self-destruction. Immune checkpoint inhibitors prevent this interaction by removing these “brakes” from the immune system.

While some immunotherapies have been successful against many cancer types when used alone, researchers are seeing even more promising results by combining them with other immunotherapies as well as standard treatments, such as chemotherapy, surgery and radiation. Gateway is currently funding three combination approach immunotherapy clinical trials.

Sacha Rothschild, MD, PhD, of the University Hospital Basel, Switzerland, is testing a combination of checkpoint inhibitors and standard chemotherapy for the treatment of non-small cell lung cancer. His Phase II clinical trial will evaluate the safety and potential efficacy of combining an anti-PD-L1 checkpoint inhibitor with cisplatin/docetaxel, a chemotherapeutic which has been shown in other studies to boost immune function.

Ulka Vaishampayan, MD, of the Barbara Ann Karmanos Cancer Institute, leads a Gateway-funded Phase II clinical trial combining checkpoint inhibitors with another immunotherapy approach – immune-modulating agents – to treat patients with metastatic prostate cancer.

In this approach, killer T-cells are activated by exposure in vitro to a signaling protein called interleukin, which strengthens and causes them to proliferate. The activated T-cells are then armed with HER2Bi-specific antibodies (BATs). When given to patients, the HER2 BATs attach to the cancer cells and, along with the checkpoint inhibitor that has removed the immune “brakes”, mount an immune offense against the disease.

In a third Gateway-funded study, Lei Zheng, MD, PhD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, is combining three approaches – a cancer vaccine, a checkpoint inhibitor, and radiation therapy to reduce cancer burden and improve quality of life in patients with advanced pancreatic cancer.

Therapeutic cancer vaccines are designed to strengthen the body’s natural immune function against cancer that has already developed by delaying or stopping cell growth, shrinking the tumor, preventing cancer reoccurrence or eliminating cancer cells that have not been killed by other forms of treatment. In this Phase II trial, Zheng and colleagues are testing the safety and potential efficacy of delivering the GVAX pancreatic cancer vaccine (developed earlier at Johns Hopkins) to activate the immune system, a checkpoint inhibitor to enhance response, and focused radiation to shrink tumors.

Two other immunotherapy approaches are Chimeric antigen receptor (CAR) T-cell therapy and therapeutic or monoclonal antibodies.

In CAR T-cell therapy, a patient’s own T-cells are genetically modified in the laboratory to express a protein called CAR, then infused back into the patient, where they locate and attach to specific proteins on cancer cells where they mount a deadly immune response.

Therapeutic antibodies are drugs designed specifically to interact with and block specific molecules that are necessary for cancer growth; bind to proteins that cause cancer cells to self-destruct; or recruit activated T-cells into close proximity with cancer cells.

In a Gateway-funded Phase I clinical trial, Christine Brown, PhD, of City of Hope Cancer Center is studying side effects and how well a CAR T-cell therapy works when given alone or in combination with monoclonal antibodies to treat glioblastoma patients whose disease has either come back or has not responded to treatment.

Sources

National Cancer Institute