Cancer Immunology & Immunotherapy

The anticancer effect of monoclonal antibodies is elicited through several mechanisms, including:

• Direct effect on tumor cells by blocking receptor initiated signaling pathways crucial for tumor cell survival and proliferation (e.g. Trastuzumab targeting HER-2/neu).
• Targeting the tumor microenvironment (e.g. inhibition of neo-angiogenesis with Bevacizumab)
• Through induction of immunological mechanisms, such as complement(CDC) or antibody (ADCC) dependent cytotoxicity, enhanced antigen presentation etc.
• Finally, a new family of monoclonal antibodies, characterized as immunomodulatory antibodies, either inhibit immunosuppressive mechanisms, checkpoint blocade (as the newly approved, on 2011, Ipilipumab which targets CTLA-4 on T cells), or antibodies enhancing the immune responses (e.g. anti-CD40, anti-OX40, anti-CD137 etc) which are currently under evaluation in several clinical trials.

Cytokines in clinical use include:

Interferon alpha (IFN-α) used in melanoma, renal cell carcinoma, CML etc

Interleukin-2 (IL-2) used for the treatment of melanoma, renal cell carcinoma, Non Hodgkin's lymphoma, leukemias etc. IL-2 has significant toxicity and enhances the expansion of regulatory T cells (Treg). Thus its replacement with other ILs is explored, such as IL-7, IL-15.

Granulocyte-macrophage colony stimulating factor (GM-CSF) is used as monotherapy for melanoma stage III and IV treatment, as well as in peripheral blood mobilization for hematopoietic stem cell transplantation and reconstitution of the myeloid lineage after chemotherapy. Additionally GM-CSF is used as an immuno-adjuvant included in many cancer vaccine trials, due to its ability to recruit and mature antigen presenting cells (DCs).

Adoptive transfer of tumor-specific T cells represent another form of immunotherapy, aiming at the rejection of the tumor. This approach has given promising results only in melanoma. Several improvements of this strategy are currently under investigation.

Recently, NK cells have also emerged as a powerful tool in cancer immunotherapy, following new studies on their biology and function. The use of alloreactive KIR-incompatible NK cells, already found to protect AML patients from relapse, represents a promising approach for the treatment of patients with different types of malignancies. Accumulating evidence from NK cell biology and function indicate that NK cells have the potential to trigger/induce tumor-specific adaptive immune responses and thus being used for the induction of "auto-vaccination" against individual tumors.

A key advance in immunology in the past decades has been the elucidation of the antigenic basis of tumor-cell recognition and destruction. As in normal cells, tumor cells express MHC-peptide antigen complexes and thus, they can elicit specific HLA-restricted immune responses. The result of such responses is the generation of cytotoxic T lymphocytes and/or antibodies against peptide epitopes derived from tumor antigens. Tumor antigens, which mostly are self antigens, fall in four categories: unique antigens (mutated, i.e. β-catenin or alternatively processed), cancer-testis antigens (normally expressed during development but aberrantly expressed in adult somatic cells, i.e. NY-ESO-1), differentiation antigens (cell-lineage-specific, i.e. Melan-A/MART-1, gp100) and overexpressed antigens (expressed in higher levels than in normal cells, i.e. HER-2/neu). Of course there are also viral antigens from viruses inducing cancer (i.e. HPV, HBV, EBV etc), but these are non-self antigens and the immune system is not normally tolerized against them.

Generating an immune response directed against a tumor antigen has several potential clinical advantages. Vaccination, if effective, would stimulate immunologic memory and could result in the prevention of relapse after standard therapy such as surgery and radiation has been administered.

In order to develop an effective immune response, the cooperation of different cell types is required: the antigen-presenting cell (APC), the CD4+ helper T cell, the cytotoxic CD8+ T cell and the antibody-producing B cell. Other cells of the innate immune system also contribute in the regulation of the immune response. Termination of an immune response in one hand and prevention of autoimmunity on the other hand, are processes that can be regulated by suppressor mechanisms which include amongst other populations, regulatory T cells, either the naturally occurring ones (natural Tregs) or committed post an immune response (adaptive regulatory T cells), myeloid -derived suppressor cells (MDSC) and soluble factors (i.e. TGF-β, IL-10, VEGF etc).  

Tumor associated-antigen (TAA) vaccines can be formulated either as peptide-vaccines, or whole proteins, tumor cells or tumor cell-lysates, TAA-RNA, dendritic cells pulsed with peptides etc.

The first vaccine approved by the FDA on April 2010 is PROVENGE®(Sipuleucel-T) (Dendreon) for asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer patients. Sipuleucel-T is a cellular immunotherapy consisting of autologous peripheral blood mononuclear cells (PBMCs), obtained by leukapheresis and cultured (activated) with a recombinant human protein (PAP-GM-CSF) consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor. The median survival time for Sipuleucel-T patients was 25.8 months comparing to 21.7 months for placebo-treated patients. Overall survival was statistically significant (p= 0.032).

Several vaccines are currently investigated in Phase III clinical trials:

GSK lung MAGE3 MAGRIT is a phase III study investigating the efficacy of MAGE-A3 (Melanoma AntiGEn-A3) Antigen-Specific Cancer Immunotherapeutic (ASCI) in preventing cancer relapse, when given after tumor resection in patients with MAGE-A3-positive stages IB, II and IIIA Non-Small Cell Lung Cancer (NSCLC).

PROSTVAC™ (Bavarian Nordic) is also in Phase III trial in minimally symptomatic castration-resistant metastatic prostate cancer patients. PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Co-administered with GM-CSF as immunoadjuvant.

PRESENT (Galena BioPharma) Phase III trial, a HER-2/neu peptide (E75) with GM-CSF as immuno-adjuvant, is currently assessing the efficacy of preventing recurrence in high risk, disease free breast cancer patients with tumors expressing low levels of HER-2/neu, after standard adjuvant therapy.

Cancer vaccines although promising as an approach, have not so far elicited dramatic clinical regressions of human tumors. Better clinical results have been obtained in early disease cancer patients to prevent recurrence. Immunoregulatory checkpoints of the host towards self-antigens, as are many of the tumor antigens, and escape mechanisms elicited by the tumor itself, impede effective anticancer immune responses. Potential avenues for overcoming these obstacles are currently under extensive investigation. The use of multi-epitope vaccines, the inactivation of regulatory factors and/or the elimination of regulatory cell populations, the use of improved immuno-adjuvants, as well as combinational and adjuvant immunotherapies, represent only a few of the approaches used to improve antitumor responses.

As for the clinical evaluation, it has become clear that the criteria (RECIST criteria) commonly used for the evaluation of other anti-cancer therapies (e.g. chemotherapy, radiotherapy, etc) do not efficiently apply in immunotherapy. This is explained by the way of action of immunotherapeutic modalities: the effective activation of the immune system against tumor requires time, during which even a transient disease progression can be observed before tumor control and/or elimination. Furthermore, immunotherapy may not totally eliminate tumor masses, but rather may lead to stable disease, by imposing an equilibrium phase between the immune system and the tumor, rendering cancer a chronically controllable disease. Thus it has been proposed that overall survival (OS) and quality of life (QoL) should be used for evaluating immunotherapy efficacy. Biological markers predicting immunotherapy outcome at earlier time points is under intense investigation worldwide.

Finally, recent evidence suggests that evaluation of the immune contexture of tumors may have better clinical prognostic value than the classical pathology TNM system in use, emphasizing the importance of the immune system in the development, progression and control of cancer.