Immunotherapy

The immune system enables 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 the body’s own cells 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 original (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 multipling and invading cancer cells.

Established (FDA approved) approaches in immunotherapy include:

  • Inmmune-Modulating/Checkpoint inhibitor Antibody  (ipilimumab): To learn more about immune-modulating antibody ipilimumab click here.
  • Humanized Monoclonal Antibody (pembrolizumab): To learn more about pembrolizumab click here.
  • Interferons: To learn about interferons (interferon alfa-2b and peginterferon alfa-2b) ) click here.
  • Interleukins: To learn about interleukins (interleukin- 2) click here.

Experimental approaches in immunotherapy include:

Immune-Modulating/Checkpoint Inhibitor Antibodies (PD-L1)

Ipilimumab (brand name Yervoy) is an immune-inhibiting antibody that works by blocking CTLA-4, a molecule on the surface of T-cells, a type of immune cell (T-lymphocyte). Normally, CLTA-4 works to slow down the immune system, thus by blocking it with ipilimumab the immune system is stimulated to attack. Two randomized trials showed that ipilimumab improved survival in patients with melanoma in combination with standard chemotherapy (dacarbazine) when compared to dacarbazine alone as well as compared with a peptide vaccine (gp100). It has been approved by the FDA (Federal Drug Administration) since 2011. It has shown prolonged survival in a large pooled analysis.

Pembrolizumab (brand name Keytruda) is a  humanized monoclonal antibody. It is designed to  block a cellular target known as PD-1, which restricts the body’s immune system from attacking melanoma cells.  In a large Phase 1 clinical trial, half of the participants received pembrolizumab at the recommended dose of 2 mg/kg. Of these patients, approximately 24 percent had their tumors shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients. A similar percentage of patients had their tumor shrink at the 10 mg/kg dose.  It has been approved by the FDA (Federal Food and Drug Administration) since 2014.

New Targets Currently Under Investigation Include:

  • PD-1 (programmed death-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. Antibodies recognizing PD-1 include nivolumab (also known as BMS-936558, MDX-1106 or ONO-4538, are currently in clinical development.  One study has shown that nivolumab can be safely combined with ipilimumab. MPDL3280A and BMS-936559 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 ipilimumab.

Adoptive T-Cell Transfer and Dendritic-Cell (DC) Transfer

Adoptive cell-transfer therapy is a method of treatment that uses the patients’ own T- cells, or DCs, which are removed and then are 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.

Adoptive T-cell transfer therapy is offered in just a few specialized centers in the world, and is still in the developmental stage. Currently there are multiple clinical trials available using different adoptive cell approaches in 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.

Tumor Cell Vaccines

These vaccines are made from melanoma cells or cell parts obtained from fresh melanoma tumors removed during surgery. As with adoptive T cell therapy, this can be a very difficult therapy to produce; only a few centers have laboratories and doctors that can produce these vaccines and the responses are not common. These remain experimental and only available in clinical trials.

Tumor cells may come from the patient, another donor or several donors

  • Autologous vaccines are made from melanoma antigens taken from a patient’s own cancer cells.
  • Allogeneic vaccines are made from melanoma tumor cells taken from individuals other than the patient.

Tumor-Associated Antigen Vaccines

Tumor-associated antigen vaccines are made from defined antigens isolated from specific tumor cells or produced by chemical or genetic synthesis. The antigens are combined with substances, cells or organisms that carry them to the immune system.

Vaccines Currently Under Investigation Include:

  • Viral Vaccines: Viruses are skilled at infecting cells and stimulating an immune response. T-VEC (talimogene laherparepvec) is a new type of the vaccine that is currently undergoing further testing. This vaccine is derived from the herpes virus but it is genetically modified in such a way 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. In addition, the action of this vaccine is enhanced by local expression of an immunostimlator, GM-CSF. The activated immune system can then fight other tumors in the body that have not been injected. The early studies showed promising results and a larger phase III study demonstrated durable response rates however it was compared with a nonstandard treatment (GM-CSF) and the trial included patients with less aggressive metastatic melanoma. An ongoing study is comparing ipilimumab versus ipilimumab in combination with talimogene laherparepvec.
  • 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 and we are awaiting the final results. A recent preliminary report stated that it did not improve disease free survival compared with placebo. Another phase III randomized trial showed the benefit of adding gp100 melanosomal antigen-derived peptide vaccine to the standard high-dose IL-2 regimen for patients with metastatic melanoma. Unfortunately this vaccine is not available for use outside of clinical trials.
  • 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, both immune-stimulating cytokines, have been approved for the treatment of patients with melanoma. Interferon is used mainly in the treatment of Stage II and III melanoma that has been surgically removed. Occasionally, it is used in the treatment of advanced metastatic melanoma. High dose interleukin-2 is approved for the treatment of advanced metastatic melanoma and is administered in the hospital over roughly 5 days. Patients must be in good physical condition to receive this treatment due to side effects which include capillary leak syndrome, hypotension and possible cardiac problems. Other immune-stimulating cytokines including IL-7, IL-12, IL-15, IL-18, and IL-21 are in clinical development for melanoma.

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.

Clinical trials for melanoma are investigating the following approaches in gene therapy:

  • 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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