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. Because cancer originates from cells in the body that have become abnormal, it is more difficult for the immune system to recognize these cancer cells as foreign invaders that should be attacked.

As the primary cancer develops and begins to multiply and invade, these cancer cells show (express) marker substances on their surfaces, known as antigens. When your immune system recognizes these antigens as a foreign invader, your body sends signals that direct your immune cells to the tissue where the new cancer cells are located, and triggers them to destroy or wall off the multiplying and invading cancer cells.

The following are FDA approved approaches in immunotherapy:

Experimental Approaches in Immunotherapy Include:

Immune-Modulating Antibodies

New Targets Currently Under Investigation Include:

  • PD-L1 (programmed death-ligand 1) PD-1 receptor is an immune inhibitory receptor expressed by activated lymphocytes. Both the receptor (PD-1) and its ligand (PD-L1) can be blocked with specific antibodies. MPDL3280A and MEDI4736 are two PD-L1 antibodies that are under investigation.
  • CD40 is a molecule on the surface of CD8 cells, which can be stimulated by a monoclonal antibody CP-870, 893. This antibody showed some activity as a single agent in patients with melanoma and is being studied in combination with CTLA-4-blocking antibodies.
  • CD137 (4-1BB) provides costimulatory signals to T-cells. Activating antibodies to CD137 induce regression of experimental tumors in animal models. An activating antibody to CD137 (Urelumab or BMS-663513) is under clinical development for melanoma and other cancers.
  • KIR Killer cell immunoglobulin-like receptors, are inhibitory molecules downregulate the immune systems’ Natural Killer cells (NK cell). Lirilumab (BMS-986015) is an antibody designed to inhibit KIR and is being investigated in combination with Yervoy.

Adoptive T-Cell Therapy (ACT) and Dendritic-Cell Therapy (DC)

ACT is a method of treatment that uses a patient’s own T- cells, or dendritic cells (DC), 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. The 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 receive high doses of chemotherapy in order to suppress the patient’s immune system so that the infused T or DC cells will not be rejected and made non-functional. Finally, the T or DC 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 impossible 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.

Recently, attempts have been made to use immune cells collected from the peripheral blood instead of those collected from the tumor. These cells were modified genetically by using retroviruses, so they could be specific for melanoma. Again, the patients receive high doses of chemotherapy before the cell infusion. Only 12% of patients responded, but more patients were eligible for this method of treatment than in the previous trial. Researchers are currently trying to improve this method.

ACT is offered in just a few specialized centers in the world, and is still in the developmental stage. Clinical trials are available using different adoptive cell approaches for patients with advanced melanoma.

Vaccines

Cancer originates from the body’s own cells and the immune system may, therefore, not be able to recognize cancer cells as foreign invaders to the same extent it does with viruses or bacteria. As a result, it may not fight cancer to the same extent it fights infections.

Vaccine, or active specific cancer immunotherapy, is an experimental form of treatment that stimulates the immune system to recognize the antigens on cancer cell surfaces as foreign invaders. Cancer vaccines are immunotherapy treatments that seek to stimulate the immune response against cancers in patients who have already developed the cancer. They are injected into the patient either under the skin, or into the blood or lymph system. These are different from vaccines used to prevent infections – cancer vaccines are not given to patients in order to prevent cancer.

It takes time for the body to build up its own defenses, so the beneficial effects of a vaccine may take months to occur. When successful, however, vaccines may promote longer-lasting tumor control or shrinkage than chemotherapy or targeted therapies and may cause fewer side effects than chemotherapy and other forms of immunotherapy such as interferon and interleukin. Unfortunately, only about 5% of patients have clinical tumor shrinkage with current cancer vaccines.

Vaccines Currently Under Investigation Include:

  • Viral Vaccines: T-VEC is a new type of vaccine derived from the herpes virus, but it is genetically modified so that it does not cause a viral infection. This vaccine is injected into the tumor, and after injection the virus is able to divide only in tumor cells causing their death. The activated immune system can then fight other tumors in the body that have not been injected. A large phase III study demonstrated a durable response rate. An ongoing study is comparing Keytruda vs Keytruda in combination with T-VEC. PV-10 is an investigational drug containing rose bengal. PV-10 is designed to be injected into the solid tumors. In a phase II study, injected tumors showed a high rate of response.
  • Peptide Vaccines: A randomized phase III trial of a peptide vaccine with the MAGE-A3 peptide in patients whose melanoma was surgically removed has completed accrual. Unfortunately, it did not improve disease free survival when compared to the placebo.
  • Dendritic cells Vaccines: Dendritic cells are powerful and effective antigen-presenting cells. They are especially efficient at alerting resting helper T-cells to the presence of foreign cells. Dendritic cell vaccines use dendritic cells to carry and present melanoma antigens to the immune system, activating an immune response.

Immune-Stimulating Cytokines

Cytokines are proteins that are secreted by numerous cells in the body and regulate many physiologic processes including immune responses. Interleukin 2 and interferon are both immune-stimulating cytokines. Other immune-stimulating cytokines including IL-7, IL-12, IL-15, IL-18, and IL-21 are in clinical development.

Biochemotherapy

Biochemotherapy is the use of immunotherapy in conjunction with chemotherapy. Clinical trials have evaluated the effectiveness of biochemotherapy as an adjuvant treatment for high-risk melanoma, and as a stand-alone treatment for advanced melanoma.

Multiple studies show that biochemotherapy may shrink tumors more frequently than single-agent or combination chemotherapy alone. There is no evidence, however, that biochemotherapy is more effective at improving overall survival compared to single-agent chemotherapy, combination chemotherapy or  single-agent immunotherapy.  As well, studies have shown that this form of therapy is associated with more severe side effects.

Given the lack of significant survival benefit in large well-conducted multicentre trials, biochemotherapy is not generally recommended for therapy except in a few special circumstances.

Gene Therapy

Gene therapy is a form of immune treatment that introduces new genetic material into damaged genes or cancer cells. The goal of gene therapy is to replace damaged cells with healthy ones or to make cancer cells more sensitive to the effects of the immune system, immunotherapy, and chemotherapy.

Approaches in gene therapy currently under investigation include:

  • Cytokines are proteins that stimulate the activity of immune cells. In one avenue of research, a patient’s melanoma cells are removed and a gene is inserted that causes melanoma cells to make cytokines. The altered melanoma cells are then injected back into the patient, with the expectation that they will trigger an immune response.
  • Gene-based immunotherapy introduces antigen genes into tumor cells in order to stimulate an immune response. Allovectin-7 is a gene-based drug that contains the antigen gene HLA-B7. When injected directly into melanoma tumors, this antigen may alert the immune system to the presence of tumor cells and trigger a local and systemic immune response against them. Preliminary results in patients with metastatic melanoma were promising. But the phase 3 trial in untreated melanoma patients that compared Allovectin-7 versus chemotherapy failed to improve response rate or survival.
  • Recombinant DNA technology, the ability to take apart and recombine a cell’s genetic information, is being investigated for use in melanoma vaccines.

Clinical Trials

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