Regression Of Melanoma Metastases Research Articles

Abstract SY32-01: The immunologic constant of rejection and cancer

Abstract The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Together with Galon's (1,2) and other groups, we propose an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells (3). As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process(4). Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Indeed, these signatures that define a good prognostic cancer phenotype are similar to those associated with the broader phenomenon of immune-mediated, tissue-specific destruction (TSD) in other immune pathologies such as regression of cancer during immunotherapy, allograft rejection, graft versus host disease, flares of autoimmunity or destruction of virally infected cells to clear intra-cellular pathogens during acute infection. Direct human observations collected by studying tissues during the acute phases of TSD demonstrated a convergence toward a common final mechanism including the activation of interferon stimulated genes, genes associated with immune effector function and the presence of a restricted group of chemokines targeting activated T and natural killer cells. We defined this set of genes “the immunologic constant of rejection” (ICR)(5,4). In cancer, it appears that the ICR genes are present not only during the acute phase of rejection, but also are expressed though with lower intensity in tumors that bear better prognosis and in tumors most likely to response to immune therapy. In particular, we recently followed a limited set of melanoma metastases undergoing immunotherapy with systemic high-dose interleukin-2. As previously observed (6), metastases that underwent complete regression following therapy differed in their transcriptional profile from non responding ones even before treatment (7) and expressed a subset of ICR genes. By serially biopsying the same metastases using minimally invasive techniques, we observed that during treatment, the responsive metastases underwent a further activation of ICR genes that was both qualitative and quantitative while the non-responding ones remained silent. This observation suggests that immune rejection of cancer is part of the intrinsic biology of individual cancers which may be predisposed to immune responsiveness and their natural history can be modulated with interventions that can enhance a naturally occurring phenomenon. It remains, however, unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Recent work from our group suggests that a combination of the two could be responsible for this multifactorial event. Analysis of two cases in which patients with melanoma experienced a mixed response during therapy suggests that the activation of ICR genes and consequently immune rejection of cancer is genetically determined by the tumor phenotypes as distinct tumors responded differently in the same patient at the same time, therefore, eliminating the genetic background of the host and/or environmental factors as determinants in these cases (8). On the other hand, recent work also from our group identified a polymorphism of the interferon-regulatory factor-5 (IRF-5) as a potential predictor of non-responsiveness to immunotherapy (9). Thus, we propose a hierarchical model of immune responsiveness in which the likelihood of a tumor to respond to immunotherapy is first dependent upon a check-point determined by the genetic background of the patient. As a second check point, in patients genetically predisposed to respond to therapy, is the genetic makeup of individual cancers that can further determine their responsiveness. Finally, as a third check point, environmental factors such as quality, intensity and type of therapy may modulate, within each cancer the likelihood of response. As several of these determinants are observed in other forms of TSD such for instance systemic lupus erythematosus, we propose, that cancer rejection in response to immunotherapy, it an aspect of auto-immunity that targets cancer-specific biological processes and it occurs only when a full-fledged acute inflammatory status is reached with complete activation of ICR genes.

Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon‐mediated rejection genes

We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress.

Hemorrhagic regression of melanoma metastases during therapeutic vaccination: a report of three cases

Melanoma metastases are characterized by pronounced neo-angiogenesis and spontaneous bleeding frequently occurring within central nervous system metastases. Clinically apparent spontaneous hemorrhage within subcutaneous melanoma metastases, however, is a rare event that coincides with progression of such metastases. We report, to our knowledge the first observation, on regression of subcutaneous metastases with hemorrhage of the overlying skin in three patients with stage IV melanoma who participated in clinical trials on therapeutic vaccination. In two patients, loss of arterial flow on Doppler ultrasound imaging was documented in the metastasis at the time of hematoma formation. One patient suffered from an intracranial hemorrhage in a subcentimetric brain metastasis coincident with the hemorrhagic regression of some of his skin metastases.

Regression of melanoma metastases following treatment with the n-bisphosphonate zoledronate and localised radiotherapy

We report a case of regression of pulmonary and bony metastases in a patient with malignant melanoma following palliative treatment with systemic zoledronate and localised radiotherapy to the bone. Zoledronate is a potent new bisphosphonate used for the treatment of metabolic bone diseases including bone metastases due to its inhibitory effect on osteoclasts. In the context of metastatic cancer zoledronate is routinely used to improve bone pain and reduce the frequency of skeletal events. There is also an increasing body of evidence suggesting that bisphosphonates exhibit anti-tumour properties. Bisphosphonates are able to activate Vgamma9Vdelta2 gamma-delta T cells which can be key players in the immune defence against malignant cells. Furthermore bisphosphonates have direct anti-proliferative, anti-metastatic and pro-apoptotic effects on tumour cells. These actions, together with their low side effect profile, may prove to be useful therapeutic tools in the treatment of cancer even in the absence of bone metastases. On the basis of this case report we here review the current literature on present preclinical and clinical studies using bisphosphonates for the treatment of cancer.

Harnessing Autoimmunity (Vitiligo) to Treat Melanoma

Melanoma is a highly malignant tumor derived from skin melanocytes (pigment-producing cells), which is associated with a significant rate of systemic metastases and death. Various therapeutic approaches for melanoma have been attempted in recent years, including the use of chemotherapy, immunotherapy, and ablative surgical and radiation treatments. However, in many cases these treatments fail as the tumor becomes resistant to the treatment and rapidly spreads and causes death. Reports in the medical literature have documented the unique immunogenic nature of melanoma where antigens, antibodies, and immune complexes seem to play a major role in the course of the disease. Anti-melanoma antibodies can cross-react with antigens on normal melanocytes, therefore causing the appearance of an associated hypopigmentation that resembles vitiligo. Vitiligo is a dermatological disorder characterized by local, dispersed, or diffuse white patches on the skin as a result of the destruction of melanocytes. This disease is believed to be an autoimmune disorder since autoantibodies against membrane components of melanocytes are found in the sera of patients with vitiligo. Melanoma triggers an anti-tumor response in many patients. Unfortunately, such anti-tumor response is insufficient to elicit tumor regression and the tumor continues to proliferate. Since the prognosis of melanoma in patients and animals with vitiligo is more favorable than in the general population, it was hypothesized that sera from patients with vitiligo may react against melanoma cells. Such studies have demonstrated that exposure of tumor cells to the sera resulted in inhibition of proliferation of the melanoma cells in vitro and in regression of melanoma metastases in mice presumably on account of the presence of the high titer of anti-melanoma antibodies in the sera used in these studies. In this review we discuss the known data and hypothetical assumptions related to the use of vitiligo-associated antibodies against melanoma, as well as characterize the immune mechanisms involved in this process.

264 ORAL Denileukin diftitox depletes T regulatory cells and causes regression of melanoma metastases in humans

264 ORAL Denileukin diftitox depletes T regulatory cells and causes regression of melanoma metastases in humans

Antigens and Antibodies in Malignant Melanoma

Antigens, antibodies and immune complexes seem to play a major role in the course of malignant melanoma, in detection of the disease progression, in treatment planning and monitoring. Of particular interest are cell and matrix adhesion molecules, growth factors and cytokines, proteases, gangliosides and major histocompatibility complex class I and II molecules. Antigens expressed on melanoma cells, but not on mature melanocytes, may be used as markers for the degree of the differentiation of the melanoma cells. The more the melanoma cells are dedifferentiated, the smaller is the antigenic similarity to normal melanocytes. Also, different antigens may be identified in various stages of the disease and may be used as tumor markers for disease recurrence or progression. Certain melanoma-associated antigens (MAA) such as epidermal growth factor receptor and adhesium molecules can be modulated by cytokines. Early melanoma evokes an antigen-derived T cell response, which becomes attenuated with the progression of the disease. A variety of cell adhesion molecules present on melanoma cell surfaces may play a role in regulation of cellular cytotoxicity. Free antimelanoma antibodies are usually not detectable in the sera of patients with melanoma, possibly due to their binding to shed antigens and formation of immune complexes or to tissue antigens. When bound to normal melanocytes, they cause the appearance of associated hypopigmentation. The identification of melanoma surface antigens led to generation of monoclonal antimelanoma antibodies (MAb) by laboratories. Strategies utilizing MAb based on immunologic approaches have been developed. MAb to tumor-associated antigens of melanoma cells may be used for therapeutic purposes in man. Sera of patients with vitiligo were capable of causing regression of melanoma metastases in mice due to the presence of a high titer of naturally occurring antimelanoma antibodies. Immunization of melanoma patients with vaccines containing treated melanoma cells or specific melanoma antigens or anti-idiotypic antibodies resulted in an increasing titer of antimelanoma antibodies and regression of the tumor to some extent. The appearance of hypopigmentation in patients with melanoma serves as proof for the activity of antimelanoma antibodies, although its association with the prognosis is still not clear. The thorough investigation in the field of MAA and related antibodies is aimed at improving specific antimelanoma immunotherapy, such as antigenic targeting or enhancement of production of autoantibodies, as well as better understanding of the process of metastasis and the melanoma-immune system interaction.