Omid Hamid, MD

For years, immunotherapy has been a beacon for patients without true results. It was based on a promise of therapy with manageable short-term toxicity leading to long-term survival. Now, immune therapy has jumped from the laboratory bench into clinical trials, and soon into the nearest oncologist’s office. With immunotherapy here to stay, we present a quick guide.

When activated by a foreign stimulus, our immune system has checks and balances that keep it from going into overdrive, attacking our bodies and causing autoimmune disease. These “inhibitory checkpoints” prevent T cells, the main workers in our immune systems, from activating. Unfortunately, cancers can use that mechanism to hide. By sending out the same signals as inhibitory checkpoints, such as PD-1 and CTLA-4, they can prevent T cells from recognizing and fighting them.

PD-1, PD-L1 and CTLA-4 inhibitors are designed to block these checkpoints so that they won’t dampen the immune system. The first approved by the FDA was Yervoy (ipilimumab), an anti-CTLA-4 treatment for metastatic melanoma. Recently, a newer class of PD-1/PD-L1 antibodies has shown remarkable benefit in a host of tumors, with the FDA approving Keytruda (pembrolizumab) and Opdivo (nivolumab) for metastatic melanoma and reviewing others for the treatment of melanoma, non-small cell lung cancer, bladder cancer and Hodgkin lymphoma.

When the immune system is attacked, it makes antibodies, proteins that are drawn like magnets to other proteins known as antigens. Once attached to antigens, which perch on the outsides of cells, antibodies call in the immune system to destroy those cells.

Monoclonal antibodies are designed in the lab to seek and destroy specific antigens, such as those on cancer cells. Single monoclonal antibodies cannot always fight tumors on their own, but bispecific antibodies have the power to bind to, and destroy, two different antigens present on one or many cells. One antibody enlists a T cell while the other targets a tumor of interest, thereby bringing the main partners of the immune process together and ensuring a response.

Recently, the FDA approved the first bispecific therapy, Blincyto (blinatumomab), which targets CD19, an antigen found in acute lymphoblastic leukemia, and the protein CD3, which is found on T cells.

Chimeric antigen receptor (CAR) therapy is designed to help T cells recognize cancer cells and attack them. It genetically modifies T cells to express a specific protein, causing them to hone in on a particular kind of cancer cell.

A patient’s own T cells are collected, then taken to the lab and manipulated to recognize and attach to a protein found only on the surface of cancerous cells. When the CAR T cells are infused into the patient’s body, they can multiply and continue to eradicate tumors. Clinical trials have shown significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma. Trials targeting a variety of other adult and pediatric malignancies are currently enrolling.

Adoptive cell transfer uses lab techniques to enhance a good immune response that is already happening in a patient’s body. A sample of a patient’s tumor is sent to a lab, where tumor-specific T cells (tumor infiltrating lymphocytes, or TILs) are stimulated to increase in number, then returned to the patient intravenously. This method has been shown to induce complete, durable regression of certain malignancies, including a number of blood cancers and melanoma.

This therapy has only been available at specialized centers, but now certain companies are working on a process that would allow surgeons to send a patient’s tumor samples to a central lab for tissue stimulation, and then receive a shipment of T cells to infuse.

—Omid Hamid is chief of translational research and immunotherapy, and director of melanoma therapeutics, at The Angeles Clinic and Research Institute in California. 

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