Immunotherapy for melanoma

What is immunotherapy?

Immunotherapy for cancer is based on the principle that the patient's immune system is capable of generating immune responses against tumor cells. Melanomas They are some of the most immunogenic tumors known, and therefore are a good model system for immune vaccine therapies. Important developments in melanoma Vaccinations over the years include:

1. understanding of antigen presentation and role of T cell activation in the generation of an antitumor response,
2. identification of a series of melanoma-specific tumors antigens that are shared by tumors from different patients, and
3. clarification of T cell recognition of specificity peptide fragments that are expressed on the surface of tumor cells.

Immunotherapy for melanoma includes several different strategies with vaccines using whole cell tumors, peptides, cytokine-mediate dendritic cellsand antibodies. Vaccines are currently being investigated to treat patients with advanced melanoma (metastatic melanoma), usually stage III (melanoma spread to regional lymph nodes) or Stage IV (extended disease).

See also Current and intralesional immunotherapy for melanoma metastasis.

The immune system

The immune system is known to function through two interdependent types of immune responses known as innate immunity and adaptive immunity.

Innate immunity

In innate immunity, an immediate immune response is activated that signals immune cells to attack and contain tumor cell antigens until a long-term and more specific response can be generated.

Adaptive immunity

Adaptive immunity is a highly specific and long-lasting response to a particular antigen. Adaptive immunity will fight the existing antigen and allow the immune system to recognize and respond more quickly to a subsequent encounter with the same antigen (immune memory).

Dendritic cells of the immune system are an important link between innate and adaptive immunity. Dendritic cells can capture antigens from surrounding tissue and, if activated, present antigens to other cells of the adaptive immune system, including T cells and B cells.

In the adaptive immune response, B cells produce antigen-specific proteins, called antibodies, to mount an antigen-specific response. T cells can become killer T cells, called cytotoxic T cells (CTL), which can directly kill foreign or aberrant cells, or mature into helper T cells, which secrete proteins that stimulate other cells to participate in the immune response.

Whole cell tumor vaccines in melanoma immunotherapy

Whole tumor vaccines have the advantage of immunizing the patient with various antigens that are present on the surface of the tumor without knowing the exact antigens that may be responsible for rejection of the tumor, that is, whole tumor cells are used as a source of antigens. .

Autologous Tumor Vaccines - Individual Patient Tailored Melanoma Vaccines

Autologous tumor cells are derived from tumors surgically removed from patients who will be vaccinated with their own engineered tumor cells. These tumor cells are irradiated or weakened in some way to prevent proliferation in the patient and reinjected in patients with or without drugs that modify the immune reaction.

One limitation for autologous tumor vaccines is that a tumor sample must be obtained from each patient. Autologous tumor vaccines require surgery resection of a sample of the patient's melanoma, which can be mechanically irradiated or destroyed and returned to the patient to promote immune recognition.

Allogeneic cellular melanoma vaccines

Vaccines have been generated using established stable cultured cell lines derived from tumors obtained from other patients. These are called allogeneic cell vaccines.

Allogeneic tumor cell vaccines have specific melanoma antigens that are shared by different patients. These shared antigens are immunogenic and may improve the hostThe immune system generates an effective antitumor response. Allogeneic vaccines also have the advantage of being more easily applicable to a larger number of patients, regardless of the availability of their own tumor cells. Two allogeneic vaccines have been evaluated in large numbers.scale, randomized trials such as assistant Therapy for melanoma.

Canvaxin® (Cancer Vax Corp, Carlsbad, CA, USA) is an allogeneic vaccine consisting of three viable irradiated melanoma cell lines. Whole cells are used. The cell lines were chosen for their high content of immunogenic melanoma and tumor associated antigens, and contained at least 11 tumor associated antigens known as MAGE-1 (melanoma associated antigen 1), MAGE-3, tyrosinase, gp100, gp75 and Mart-1 (T-cell recognized melanoma associated antigen) / Melan-A. Multicenter randomized controlled trials compared Canvaxin plus BCG with placebo plus BCG in patients with stage III and stage IV melanoma in a postoperative state of resection. The phase III trial for stage III melanoma patients reached the target number of enrollments and was closed in September 2004. The phase III trial for stage IV patients closed early, in April 2005. The development of Canvaxin was discontinued in the US Results of clinical trials determined that the vaccine was unlikely to increase survival in stage III disease.

Melacine® (Ribi ImmunoChem Research, Inc., Hamilton, MT, USA). Melacin consists of a mixture of two homogenized melanoma cell lines that are combined with DETOX adjuvant ("detoxified Freund's adjuvant" comprising monophosphoryl lipid A and purified mycobacterial cell wall skeleton). Based on studies in patients with stage IV melanoma, Melacine was approved in Canada in May 2000 to treat advanced melanoma.

Defined antigen vaccines in melanoma immunotherapy

Allogeneic and autologous melanoma vaccines provide numerous potential antigens, but the most important antigens remain unknown and monitoring the immune response has been challenging. The use of defined antigens has made it possible to measure the specific immune responses of these antigens.

Ganglioside vaccines in melanoma immunotherapy

Defined tumor antigens can be created synthetically. Various cell surface molecules in melanoma cells they can be targeted by antibodies, and antibodies against some of these molecules are induced in melanoma patients.

A number of clinical studies have been conducted with vaccines intended to induce B cell or humoral responses to the melanoma antigen, GM2, a cell surface ganglioside. In a pilot study, Livingston and colleagues showed a trend toward better survival for patients with stage III disease receiving low-dose GM2 / BCG ganglioside chemotherapyand they showed that the patients developed antibodies against the ganglioside GM2. This led to a larger randomized phase III ECOG (Eastern Cooperative Oncology Group) study comparing GM2 / KLH (keyhole limpet hemocyanin with xenogeneic protein (KLH) in the adjuvant saponin-derived QS-21 vaccine with high-dose interferon ( IFN) α-2b This study was recently closed due to higher survival rates in those treated with adjuvant IFN α-2b.

Peptide vaccines in melanoma immunotherapy

Peptide vaccines are intended to stimulate cell (T cell) mediated responses to tumor specific antigens expressed on the surface of cells through a class I restricted major histocompatibility complex (MHC) process.

Most peptide antigens are weakly immunogenic, so they are generally administered to the patient together with an immune adjuvant. These adjuvants, such as BCG or "incomplete Freund's adjuvant," are intended to induce inflammation and start the immune process.

Cytokines, as interleukin (IL) -12 or granulocytes macrophageColony Stimulating Factor (GM-CSF) has also been administered concurrently with these vaccines to further stimulate the immune response.

Melanoma cells can escape recognition and destruction by the immune system by hiding their antigens. Melanoma cells from different individuals express different antigens. Therefore, vaccines with multiple antigens may be more effective than those composed of a single antigen.

Clinical trials with peptide vaccines with epitopes MAGE-1, MAGE-3, MART-1, gp100, tyrosinase, and gp75 have been used for the immunization of stage III and IV patients.

Peptide heat shock vaccines in melanoma immunotherapy

A recent approach is to use heat shock peptide protein complexes (HSPPC) as vaccines. Heat shock proteins are stress proteins that "protect" antigenic proteins, alerting the immune system to eliminate disease.

Peptide complexes extracted from melanoma cells can stimulate antigen-specific CD8 + T cells in the peripheral blood from melanoma patients. Preliminary data have indicated feasibility, minimal toxicity, and clinical responses in 18% of the patients along with tumor specific T cell responses in 50% to 60% of the subjects.

Currently, a phase III study is comparing a heat shock peptide vaccine (HSPPC-96) derived from an autologous tumor with standard therapies (IL-2-based therapy and / or dacarbazine / temozolomide and / or complete tumor resection) in patients with stage IV melanoma.

CpG DNA melanoma immunotherapy vaccines

TLR9 is a toll receiver found in some immune cells (dendritic cells and B cells). Recognize a specific pattern of nucleotides found in bacteria and viruses known as CpG DNA. Synthetic CpG DNA agonists have been developed that bind and activate TLR9.

TLR9 agonists initiate a cascade of cellular signals that result in a highly specific, innate and adaptive immune response targeting infections and tumors, by generating cytotoxic T cells and disease-specific antibodies. TLR9 agonists activate dendritic cells to fight the development of immune tolerance to pathogens and cancers.

CPG 7909 is a single-stranded oligodeoxynucleotide TLR9 agonist that is being studied as an adjunct to melanoma chemotherapy. A phase II study in patients with advanced melanoma has been completed and a phase III study will begin in patients with unresectable stage IIIb / c or stage IV melanoma.

Monoclonal CTLA4 antibody in melanoma immunotherapy

Cytotoxic Tlymphocyteassociated antigen 4 (CTLA4) decreases T-cell function and therefore reduces the effectiveness of cancer vaccines. Ipilimumab is a monoclonal antibody that blocks CTLA4 and has been shown to increase tumor immunity in previously vaccinated stage IV melanoma. To date, the side effects of ipilimumab have included the skin. rashes and itching in one third of patients.

A randomized, double-blind phase III trial evaluated the effectiveness of ipilimumab alone or in combination with an MDX-1379 vaccine (a peptide vaccine composed of two peptides of the melanoma protein gp100). Because these peptides bind to HLA-A2, which is recognized by T cells, only previously treated stage III or IV melanoma patients (with unresectable disease) who are positive for HLA-A * 0201 were eligible. The recently published results of this trial have demonstrated a significant overall survival benefit with ipilimumab compared to a cancer vaccine comprising HLA-A * 0201 restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100) in patients with metastatic melanoma, previously unsuccessfully treated with aldesleukin, dacarbazine, temozolomide, fotemustine or carboplatin.

Based on the results of the phase III study, the US Food and Drug Administration (FDA) approved ipilimumab to treat patients with late-stage (metastatic) melanoma in March 2011. Ipilimumab is the first therapy approved by the FDA clearly demonstrating that metastatic melanoma patients live longer on this treatment. The therapy is being approved with a risk assessment and mitigation strategy to inform healthcare professionals and patients about the risks of the treatment.

Cytokine and growth factor modulation in melanoma immunotherapy

Cytokines are soluble proteins that are important in the regulatory function of cells of the immune system. Cytokines that have been used clinically to treat cancer patients include IL-2, IFN-α, IFN-β, IFN-γ, GM-CSF, and TNF (tumor necrosis factor).

• Recombinant IL-2 intravenous administration has been used in clinical trials for patients with metastatic melanoma with overall response rates of approximately 20%.
• Recombinant humanized (rh) GM-CSF was used in addition to the autologous tumor vaccine to treat metastatic melanoma patients with response rates of 20% and a complete response rate of 10%.
• The FDA has approved IL-2 and INF-α for the treatment of melanoma. However, there are significant side effects including flu-like symptoms, muscle aches, skin eruption, fever, weakness, nausea and diarrhea.

Administration of vaccines against melanoma.

Nursing advice for melanoma vaccines should include:

• do not inject into a limb that had primary melanoma
• rotate injection sites
• warn the patient of possible flu-like symptoms
• observe the patient for sterility abscess or infection at the injection site
• instruct the patient to expect a minor located pain, irritation, swelling, and discomfort at the injection site
• evaluate and document the patient allergy history
• follow strict preparation and administration guidelines
• use correct path: deep subcutaneousintramuscular or intradermal injection
• select needle caliper according to study protocol
• some protocols suggest that corticosteroids or immunosuppressive medications should not be given to the patient while on the vaccine
• monitor the patient for magnification lymphadenopathy (Swollen lymph glands)

Conclusions

There is a significant collaborative effort in the United States and Europe involving the National Cancer Institute, pharmaceutical companies, hospitals, and cancer vaccine research and development institutes. More than 95 tumor vaccines are being developed, many of which are for the treatment of patients with melanoma.

Currently, the only immunotherapies Approved by the US FDA for the treatment of melanoma are IL-2, INF-α2a, and ipilimumab. Currently, no melanoma vaccine has received FDA approval. A search of the National Institute of Health clinical trials database reveals several phase III trials and many phase I and II trials investigating a variety of vaccines as monotherapy or in combination with other chemotherapy agents for the treatment of melanoma. .

The current use of melanoma tumor vaccines (June 2011) is not included in the 2010 National Comprehensive Cancer Network practical guide for the treatment of melanoma. The American Cancer Society (2010) noted that "vaccines are experimental therapies that do not yet have a proven benefit."

Note to readers

This article was written in June 2011. Immunotherapy for melanoma is a rapidly evolving field and information can quickly become out of date.