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 flu virus, and that’s why you recover from a cold,
But cancer cell have several ways of killing or inhibiting your immune system so that they cannot do their job, and that is why the immune system often does not recognize the cancer cells, which can then continue to grow unchecked.
This occurs partly because cancer cells use several mechanisms of hiding from the immune system to make them undetectable. As the cancer cells develop and begins to multiply and invade, they express marker substances on their surfaces, known as antigens. Ideally, your immune system should recognize these antigens as a foreign invader and kill the cancer cells. But the cancer cells block the immune system from recognizing them as foreign invaders that should be attacked.
Immunotherapy consists of a class of drugs that block this interaction between your cancer cells and your immune cells, so that your immune cells can do their job.
The following are FDA approved approaches in immunotherapy:
- Interferons: Learn about Intron A and Sylatron by clicking here.
- Checkpoint inhibitor immunotherapy: Learn about Yervoy by clicking here. Learn about Keytruda and Opdivo by clicking here.
- Combination immunotherapy: Learn about the combination of Ipilimumab and Nivolumab by clicking here.
- Interleukins: To learn about Proleukin/IL-2 by clicking here.
- T-VEC is a form of immunotherapy that is injected into the tumor. Learn about T-VEC by clicking here.
Experimental Approaches in Immunotherapy Include:
There are several new targets that are currently under investigation. As well, 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. Nivolumab and pembrolizumab, which target the PD-1 receptor, are explained in the ‘FDA approved approaches’ section, above. Atezolizumab and Durvalumab are two PD-L1 antibodies that are under investigation. Atezolizumab is also being investigated in combination with cobimetinib (see ‘Targeted therapy’ section) in a large phase III trial.
- 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 nivolumab (Opdivo) 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 this combination has completed enrollment and the addition an IDO inhibitor to Keytruda did not appear to approve response rates.
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 nivolumab (Opdivo) 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 ipilimumab (Yervoy) and nivolumab (Opdivo), though results to date have not been very promising in other disease types.
- GITR is expressed on the surface of activated immune cells. TRX518 (an anti-GITR antibody) is currently being evaluated in a phase I study in patients with stage III/IV melanoma.
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, immunotherapy and sometimes radiation.
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 this can be a very difficult therapy to produce; only a few centers have laboratories and doctors that can accomplish this. 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.