What is Immunotherapy?

The immune system allows your body to distinguish its own healthy cells from abnormal or foreign cells and organisms. These foreign invaders include viruses, bacteria, and other disease-causing organisms. For example, your immune system will usually recognize a cell that is infected with a virus, and that’s why you recover from a cold, but the immune system has a tougher time targeting cancer cells. 

There are limits on the immune system’s ability to fight cancer on its own, because many people with healthy immune systems still develop cancer. Sometimes the immune system doesn’t see the cancer cells as foreign because the cells aren’t different enough from normal cells. Sometimes the immune system recognizes the cancer cells, but the response might not be strong enough to destroy the cancer. Cancer cells themselves can also give off substances that keep the immune system in check. To overcome this problem, researchers have found ways to help the immune system recognize cancer cells and strengthen its response so that it can destroy them. Immunotherapy is a treatment that uses certain parts of your immune system to fight diseases such as melanoma by:

  • Stimulating your own immune system to work harder or smarter to attack cancer cells.
  • Giving your immune system components, such as man-made immune system proteins, to fight the cancer cells.

Some types of immunotherapy are also called biologic therapy or biotherapy.

Types of Melanoma Immunotherapy

The main types of immunotherapy now being used to treat melanoma include: 

  • Immune checkpoint inhibitors: These medications are monoclonal antibodies designed to target receptors on the surface of immune cells to either activate or inhibit their function. Yervoy (ipilimumab), opdivo (nivolumab) and keytruda (pembrolizumab) are examples that act by basically taking the ‘brakes’ off the immune system, which helps immune cells recognize and attack cancer cells.
  • Cancer vaccines: Vaccines are substances put into the body to start an immune response against certain proteins or parts of cancer. We usually think of them as being given to healthy people to help prevent infections, but some vaccines can help prevent or treat cancer. 
  • Cellular therapies: Cellular therapies use a patient’s own immune cells that are removed from the body, processed in a lab with a goal to help these cells be more effective fighting cancer, and then re-infused into the patient’s body. These types of therapies include tumor-infiltrating lymphocytes (“TILs”) and chimeric antigen receptor (CAR) T-cell therapy. These therapies are not FDA approved and are under investigation on clinical trials. 
  • Many novel immune therapies are in early stages of development to determine safety, toxicity, and efficacy and are under investigation on clinical trials. 

FDA Approved Immunotherapy Drugs for Melanoma

The following are FDA approved approaches in immunotherapy:

  • Interferons:  Intron A (interferon) and Sylatron (peginterferon alfa-2b) (note: discontinued)
  • Checkpoint inhibitor immunotherapy:  Yervoy, Keytruda and Opdivo
  • Combination immunotherapy:  Yervoy and Opdivo
  • Immunotherapy combined with targeted therapy: Tecentriq (immunotherapy), Cotellic and Zelboraf (targeted therapy combination)
  • Interleukins: Proleukin/IL-2 (interleukin-2)
  • Vaccine: Imlygic (talimogene laherparepvec “T-VEC”) is a form of immunotherapy that is injected into the tumor (see vaccines for more information on T-VEC)

Experimental Approaches in Immunotherapy Include: 

Immune-Modulating Antibodies

There are several new targets that are currently under investigation. Additionally, several of these new targets are also being tested in combination with already approved therapies for the treatment of patients whose melanoma has stopped responding to immunotherapy treatment with anti-PD1 and/or anti-CTLA4. The hope is that by combining these agents it will lead to higher response rates.

Inhibitory checkpoint molecules:

PD-L1 (programmed death-ligand 1) is expressed on tumor cells, and binds to the PD-1 receptor, which is an immune inhibitory receptor expressed by activated lymphocytes (a kind of cell in the immune system). When PD-L1 binds to PD-1, it inhibits the ability of the immune cell to kill the tumor cell. Thus, PD-L1 acts as a sort of ‘tumor shield’. Both the receptor (PD-1) and its ligand (PD-L1) can be blocked with specific antibodies. Opdivo and keytruda, which are explained in the FDA Approved Drugs section of this website, target the PD-1 receptor. Atezolizumab and Durvalumab are two PD-L1 antibodies that are under investigation. See Targeted Therapy and FDA Approved Drugs sections of this website for more information.

TIM-3 is expressed on activated T cells and regulates immune function. On binding to certain proteins, TIM-3 triggers death of the immune cells. Thus, TIM3 functions as a negative regulator of T cell function. TIM-3 antibodies are being evaluated in patients with advanced melanoma, in combination with anti-PD1 antibodies.

LAG3 is also expressed on immune cells, and negatively impacts cellular proliferation and activation. BMSl-986016 (a LAG3 antibody) was tested in combination with Opdivo (nivolumab) in patients whose disease had progressed on anti-PD1 alone, and preliminary data are encouraging.

IDO is an enzyme found inside certain cells. It negatively affects T cell function by depleting tryptophan, allowing tumor cells to ‘escape’ the immune system. A phase III study to evaluate the addition of an IDO inhibitor to Keytruda did not decrease the likelihood of the cancer continuing to grow compared to pembrolizumab by itself. 

Stimulatory checkpoint molecules:

CD40 is a molecule on the surface of immune cells and plays a role in activating T cells. In a phase I study, CP-870,983 (a CD40 antibody) showed some activity in combination with tremelimumab (a CTLA-4-blocking antibody). A phase I/II study is evaluating APX005M (a CD40 antibody) in combination with Opdivo (nivolumab) in patients with advanced melanoma and non-small cell lung cancer.

4-1BB (CD 137) provides costimulatory signals to T-cells. Urelumab, a CD137 antibody showed promising results when combined with nivolumab in patients with advanced melanoma.

KIR Killer cell immunoglobulin-like receptors are inhibitory molecules that downregulate the immune systems. Lirilumab (BMS-986015) is an antibody designed to inhibit KIR and has been investigated in combination with Yervoy (ipilimumab) and Opdivo (nivolumab), though results to date have not been very promising in other disease types.

Adoptive T-Cell Therapy (ACT)

ACT is a method of treatment that uses a patient’s own T- cells, which are removed and then grown, expanded, and modified in a laboratory to improve their function. These cells are then infused back into the patient in combination with other therapies such as chemotherapy and immunotherapy.

The majority of clinical trials have used TILs (tumor-infiltrating lymphocytes), the immune cells that are present within the tumor, to generate the T-cell treatment. Patients who are treated with this method must first undergo surgical resection of the tumor; then TILs are isolated from the tumor cells in the laboratory, expanded in number, and modified in the laboratory. When the cells are ready for infusion, the patient must first receive high doses of chemotherapy in order to suppress the patient’s immune system so that the infused T cells will not be rejected and made non-functional. Finally, the T cells are infused into the patient.

In one clinical trial, more than 50% of the patients responded to the therapy, although the selection of patients and lack of general access to such treatments makes it difficult to generalize these results at this time. These responses are very exciting, but ACT can be a very difficult therapy to produce: Only a few centers have laboratories and doctors that can provide it. In addition, many patients are not healthy enough to tolerate this rigorous form of therapy. This approach has also been evaluated for patients with Stage IV uveal melanoma, with promising results.

Learn more about all FDA approved immunotherapy drugs for melanoma.