Subcutaneous Melanoma Metastases Research Articles

Immediate results
 of electrochemotherapy for malignant
 tumors of the skin and soft tissues,
 cutaneous and subcutaneous metastases
 of melanoma

Relevance: Surgical removal of locally advanced forms of
 skin cancer and multiple cutaneous and subcutaneous metastases of melanoma does not always provide satisfactory aesthetic,
 functional, and long-term results. The treatment outcomes depend on the size, shape, location, and some other characteristics
 of the tumor. The relapse rate after surgical removal of locally
 advanced skin cancer is 12.5-34%, and the long-term survival of
 patients with cutaneous and subcutaneous metastases of melanoma does not exceed 30%. Cutaneous and subcutaneous metastases of melanoma and some superficial tumors are usually
 initially inoperable. Their complications such as bleeding, infection, pain, and pitting cause serious clinical problems and often
 require local therapy even at the 4th stage of the disease.
 Electrochemotherapy (ECT) is one of the modern treatment
 methods for skin cancer, soft tissue sarcoma, and metastatic melanoma. ECT is a treatment of choice in the presence of
 contraindications to surgical and radiation therapy. ECT combines the physical properties of current-induced electroporation with the chemical properties of chemotherapeutic drugs.
 In this method, an electric current affecting the tissue causes
 a temporary increase in cell membrane permeability, thereby
 providing free access to the cell of large molecules, including
 cytostatics, which are not initially transferred to the cytosol.
 This significantly increases the potential toxicity of cytostatics.
 The purpose of this study was to demonstrate the immediate results of ECT in patients with malignant tumors of the
 skin, soft tissue, cutaneous, and subcutaneous melanoma metastases.
 Results: Since 2017, 27 patients were treated by ECT at
 the Centre for bone and soft tissue tumors and melanomas
 of Kazakh Institute of Oncology and Radiology (Almaty, Kazakhstan). After two months, 67% of patients had a complete
 response (CR), 26% – a partial response (PR), and 7% had progression of the tumor. Side effects included local edema (n=13,
 40%) which independently disappeared within several days
 to 2 weeks, local pains (12%) which disappeared within six
 months after treatment in 3% and within a month in 11% of
 patients, and hyperthermia in the early postoperative period in
 6% of patients which was stopped within 10-15 min after the
 procedure

Immediate results of electrochemotherapy for
 malignant tumors of the skin and soft tissues,
 cutaneous and subcutaneous metastases
 of melanoma

Relevance: Surgical removal of locally advanced forms of skin cancer and multiple cutaneous and subcutaneous metastases of melanoma does not always provide satisfactory aesthetic, functional, and long-term results. The treatment outcomes
 depend on the size, shape, location, and some other characteristics of the tumor. The relapse rate after surgical removal of
 locally advanced skin cancer is 12.5-34%, and the long-term survival of patients with cutaneous and subcutaneous metastases
 of melanoma does not exceed 30%. Cutaneous and subcutaneous metastases of melanoma and some superficial tumors are
 usually initially inoperable. Their complications such as bleeding, infection, pain, and pitting cause serious clinical problems
 and often require local therapy even at the 4th stage of the disease.
 Electrochemotherapy (ECT) is one of the modern treatment methods for skin cancer, soft tissue sarcoma, and metastatic
 melanoma. ECT is a treatment of choice in the presence of contraindications to surgical and radiation therapy. ECT combines
 the physical properties of current-induced electroporation with the chemical properties of chemotherapeutic drugs. In this
 method, an electric current affecting the tissue causes a temporary increase in cell membrane permeability, thereby providing
 free access to the cell of large molecules, including cytostatic drugs, which are not initially transferred to the cytosol. This significantly increases the potential toxicity of cytostatic drugs.
 The purpose of this study was to demonstrate the immediate results of ECT in patients with malignant tumors of the skin,
 soft tissue, cutaneous, and subcutaneous melanoma metastases.
 Results: Since 2017, 27 patients were treated by ECT at the Centre for bone and soft tissue tumors and melanomas of Kazakh Institute of Oncology and Radiology (Almaty, Kazakhstan). After two months, 67% of patients had a complete response
 (CR), 26% – a partial response (PR), and 7% had progression of the tumor. Side effects included local edema (n=13, 40%)
 which independently disappeared within several days to 2 weeks, local pains (12%) which disappeared within six months in 3%
 and within a month after treatment in 11%, and hyperthermia in the early postoperative period in 6% of patients which was
 stopped within 10-15 min after the procedure.

ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death

Rationale: The development of a highly effective and tumor-specific therapeutic strategy, which can act against the primary tumor and also condition the host immune system to eliminate distant tumors, remains a clinical challenge.Methods: Herein, we demonstrate a facile yet versatile ZnO-capping and Doxorubicin (DOX)-loaded multifunctional nanocomposite (AuNP@mSiO2@DOX-ZnO) that integrates photothermal properties of gold nanoparticles (NPs), pH-responsive properties and preferential selectivity to tumor cells of ZnO QDs and chemotherapeutic agent into a single NP. The photothermal performance, pH-triggered release and preferential phagocytic ability were assessed. The induced anti-tumor immunity was determined by analyzing immune cell profile in tumor in vivo and molecular mechanism were identified by detecting expression of immunogenic cell death (ICD) markers in vitro. Moreover, mice models of unilateral and bilateral subcutaneous melanoma and lung metastasis were established to evaluate the antitumor effects.Results: As an efficient drug carrier, ZnO-capped NPs guarantee a high DOX payload and an in vitro, efficient release of at pH 5.0. In murine melanoma models, the nanocomposite can significantly inhibit tumor growth for a short period upon low-power laser irradiation. Importantly, ZnO NPs not only demonstrate preferential selectivity for melanoma cells but can also induce ICD. Meanwhile, AuNP@mSiO2-based photothermal therapy (PTT) and DOX are directly cytotoxic towards cancer cells and demonstrate an elevated ICD effect. The induced ICD promotes maturation of dendritic cells, further stimulating the infiltration of effector T cells into tumor sites, preventing tumor growth and distant lung metastases.Conclusions: This study highlights the novel mechanism of ZnO-triggered anti-tumor immunity via inducing ICD. Additionally, we shed light on the multifunctionality of nanocomposites in delivering localized skin tumor therapy as well as inhibiting metastatic growth, which holds great promise in clinical applications.

The advent of oncolytic virotherapy in oncology: The Rigvir® story

Oncolytic viruses are a fast-developing cancer treatment field. Numerous viruses have been tested in clinical trials and three are approved. The first, Rigvir, is an immunomodulator with anti-tumour effect for treatment of melanoma, local treatment of skin and subcutaneous metastases of melanoma, for prevention of relapse and metastasis after radical surgery registered in Latvia, Georgia, Armenia and Uzbekistan. The aim of the present review is to summarize the development of Rigvir. Approximately 60 viruses were screened preclinically. Clinical safety and efficacy trials were with 5 oncolytic enteroviruses. Safety of the selected and melanoma-adapted ECHO-7 virus Rigvir was tested in over 180 patients with no severe adverse events observed. Pre-registration efficacy studies involved over 700 cancer patients: over 540 melanoma patients, and patients with late stage stomach (ca. 90), colorectal cancer (ca. 60), and other cancers. Patients were treated with Rigvir for 3 years after surgery and compared to immunotherapy: 3- and 5-year overall survival appeared to be increased in Rigvir treated patients. In post-marketing retrospective studies, Rigvir-treated stage II melanoma patients showed a 6.67-fold decreased risk for disease progression in comparison to those that had been observed according to guidelines, and stage IB and stage II melanoma patients that had received Rigvir therapy had 4.39–6.57-fold lower mortality. The results are confirmed and extended by case reports. Several immunological markers have been measured. In conclusion, Rigvir is an oncotropic and oncolytic virus for treatment of melanoma; the results will be confirmed and updated by modern clinical studies.

Abstract CT021: Phase Ib study of a novel immunotherapy combination therapy of intralesional coxsackievirus A21 and systemic ipilimumab in patients with advanced melanoma

Abstract Background: CVA21 (CAVATAK) is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21. Intratumoral (i.t.) CVA21 injection can induce preferential tumor cell infection, tumor immune-cell infiltration, up-regulation of γ-INF response genes, cell lysis and enhancement of a systemic anti-tumor immune response. Pre-clinical studies in an immune-competent mouse model of melanoma have revealed that combinations of intralesional CVA21 and anti-CTLA-4 or anti-PD-1 mAbs mediated significantly greater antitumor activity and compared to use of either agent alone. Presented are the interim data of the open-label, multicenter Phase Ib MITCI (Melanoma Intra-Tumoral Cavatak and Ipilimumab) study of novel immunotherapy combination Coxsackievirus A21 and ipilimumab in patients with advanced melanoma Methods: The Phase Ib MITCI study (NCT02307149) is investigating the efficacy and safety of i.t. CVA21 and i.v. ipilimumab in 26 patients with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Pts received up to 3 × 10e8 TCID50 CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipilimumab (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Treatment is continued until DLT, intolerance, all injectable tumors disappeared, or confirmed disease progression (PD) per immune-related (ir) WHO response criteria. The first response assessment occurs at study Day 106. Key eligibility criteria were ? 18 yrs old, ECOG PS 0-1, and at least 1 injectable cutaneous, subcutaneous, or nodal melanoma metastasis ? 1.0 cm. The primary endpoint was to assess safety of CAVATAK in combination with scheduled ipilimumab treatment. Secondary endpoints included irWHO objective response rate (ORR), responses in injected and non-injected lesions, durable response rate (continuous response ? 6 mos), median time to initial response, survival and QOL. Results: At present, of the 7 patients enrolled, no DLT's have been reported. Combination treatment has been generally well-tolerated with only 2 Gr 3 AEs reported, one with ipilimumab-related fatigue and the other with unrelated hypertension. Of 5 pts with investigator assessed response, ORR was 80%, with all responses occurring by 3.5 months and in both injected and non-injected lesions. Responses were observed in patients with Stage IIIC and Stage IV M1a/c disease. Response rates in individual injected and non-injected lesions were 80% (n = 10) and 87% (n = 15), respectively. Complete tumor responses were observed in some visceral and non-visceral lesions. Patients developed notable levels of anti-CVA21 serum neutralizing antibody by Day 22. Conclusions: Intralesional CVA21 + ipilimumab is a promising novel oncolytic immunotherapeutic combination for the treatment of unresectable Stage IIIC-IVM1c melanoma. At present no DLT has been achieved, with no Gr 3/4 CVA21-related AEs observed. The preliminary overall response rate (80%) is higher than published rates for either agent used alone (CVA21: 28.1% and ipilimumab:∼15-20%) in advanced melanoma patients. The combination immunotherapy treatment is generally well tolerated and has displayed antitumor activity in both local and systemic disease, also within environments of high levels of anti-CVA21 serum neutralizing antibody. Citation Format: Brendan Curti, Jon Richards, Mark Faries, Mark Grose, Roberta Karpathy, Darren R. Shafren. Phase Ib study of a novel immunotherapy combination therapy of intralesional coxsackievirus A21 and systemic ipilimumab in patients with advanced melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT021.

Patient-derived tumor xenograft strategies for informed management of patients with metastatic melanoma.

Metastatic melanoma has benefited from immunotherapy and targeted therapy advances. Faced with the inescapable onset of treatment resistance, the choice of a second-line treatment can be guided by a patient-derived tumor xenograft (PDTX). This new approach requires an excellent multidisciplinary collaboration where the surgeon has a key role to play. Each patient included (stage IIIC or IV) presented with subcutaneous melanoma metastasis that could be surgically resected. The surgeon performed orthotopic PDTX on CB17-SCID mice. To validate the model, tumor material was amplified over three successive generations of animals to obtain cohorts compatible with carrying out a study to compare treatment response by targeted therapy (vemurafenib versus controls). Tumors were characterized (histologically and genetically) at all stages of the generations' amplification. Functional imaging by fluorine-18 fluorodeoxyglucose PET scan was performed for the third generation PDTX. Seventeen patients with a mutated BRAF V600E subcutaneous metastasis were included, yielding 257 PDTX. Clinical, histological, and genetic characteristics of the grafted tumors were stable over the three mice generations. The treatment response to vemurafenib was observed for all PDTX. The fluorine-18 fluorodeoxyglucose PET scan evidenced a decreased in glucose uptake in the treated tumors. PDTX models are being widely used in fundamental research and are more compatible with clinical issues. If PDTX are simple and easily reproducible in metastatic melanoma, an organized multidisciplinary platform is essential to implement them. In our experience, surgeons have a key role to play in the cohesion of this new therapeutic approach.

Calm Study: Secondary Endpoints of a Phase Ii Study of a Novel Oncolytic Immunotherapeutic Agent, Coxsackievirus A21, Delivered Intratumorally in Patients with Advanced Malignant Melanoma

ABSTRACT Aim: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21. Following intratumoral injection, CAVATAK preferentially infects ICAM-1 expressing tumor cells, resulting in cell lysis and a systemic anti-tumor immune response. We here report on the key secondary endpoints in the Phase II CALM study. Methods: The CALM study investigated the efficacy and safety of intratumoral CAVATAK in 57 patients with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Patients received up to 3 x 108 TCID50 CAVATAK intratumorally on study days 1,3,5 and 8 and then every three weeks for a further 6 injections. Patients displaying immune-related progression-free survival (irPFS) or better at 6 months were eligible for 9 additional injections. Key eligibility criteria were ECOG 0-1, and at least 1 injectable cutaneous, subcutaneous, or nodal melanoma metastasis >1.0 cm. The primary endpoint was to achieve >9 of 54 evaluable patients with irPFS at 6 months. Secondary endpoints included median irPFS, 1-year survival, median time to response, irRECIST 1.1 best overall response (BORR) and safety. Results: The primary endpoint of the study was achieved with 19 of 51 (37.3%) evaluable patients displaying irPFS at 6 months. Preliminary analysis of secondary endpoints showed: median irPFS of 4.2 months (95% CI 2.8, 8.3), 1-year survival 61.5% (16 of 26 pts), on-going BORR (irRECIST 1.1) 26.3% (15 of 57 pts) with responses seen in both injected and non-injected lesions, median time to response 2.8 months. To date 15 patients have received additional series of CAVATAK injections. The most common patient side effects observed were Grade 1 local injection site reactions, fatigue, chills and fever. There were no Grade 3 or 4 product-related AE's. Conclusions: Intralesional CAVATAK is a promising novel oncolytic immunotherapeutic agent with limited toxicity and robust responses in both injected and non-injected lesions in patients with advanced melanoma. The effectiveness of CAVATAK warrants additional investigation as monotherapy and in combination with other targeted immunotherapies such as immune checkpoint blockade. Disclosure: R.H. Andtbacka: Travel honorarium–Viralytics; K. Zhou: Salary - Viralytics J.I. Weisberg: Salary–Viralytics; D. Shafren: Stock, salary–Viralytics. All other authors have declared no conflicts of interest.

Electrochemotherapy: an effective local treatment of cutaneous and subcutaneous melanoma metastases

Treatment of multiple cutaneous and subcutaneous melanoma metastases is still represents a therapeutic challenge for both dermatologists and oncologists. Electrochemotherapy (ECT) is a promising therapeutic procedure, owing to its ability to improve the penetration of cytotoxic drugs into cancer cells by application of current electric pulses. The aim of our study is to evaluate efficacy, tolerability and long-term efficacy of ECT in the treatment of advanced metastatic melanoma. Thirty patients affected by a total of 654 cutaneous and subcutaneous melanoma metastatic nodules were recruited. All patients were treated after they had undergone to a mild general anesthesia. Intravenous Bleomicina solution was administered 8 minutes before the application of electric pulses, generated by a Cliniporator (TM) (the device validated for ECT). The objective response rate of 100% (67.28% complete response and 32.72% partial response) was observed. A total of 214 metastatic lesions from 24 patients received a second ECT session, among them 141 showed a further complete response. Twenty-four months later, the local tumor control rate was 72%. The results of this study seem to demonstrate that ECT is an effective and valid therapeutic tool for the treatment of cutaneous metastases from melanoma. ECT can be considered a first-line palliative treatment since it is able to alleviate pain and reduce the tumor's spontaneous bleeding with a significant improve of patients' quality of life.

Evaluation of the safety and immunogenicity of intratumoral injection of interferon gamma (IFNg) during vaccination in patients with subcutaneous or cutaneous metastases of melanoma (Mel51; NCT00977145).

TPS3118^ Background: One mechanism to improve immunologic outcomes of vaccine therapy, and other immune therapies, is to optimize T cell trafficking to sites of tumor. CXCR3 is expressed by Th1 and Tc1 T cells and directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC)) are induced by interferon gamma (IFNg). This protocol tests whether administering peptide vaccine activates circulating tumor antigen-specific CD8+ CXCR3+ T cells, followed by intratumoral IFNg to increase CXCR3 ligands (CXCL9-11) at the tumor site and thus to recruit the CXCR3+T cells. Methods: This pilot clinical trial is enrolling patients (n=14) with subcutaneous or cutaneous metastases of melanoma (stage IIIB-IV), who have adequate accessible tumor in 1-4 lesions to provide 100-300 mm3 tumor on each of the three biopsy days, and with at least one lesion amenable to intratumoral IFNg injection. Patients must also express HLA-A1, A2, A3, or A11. Patients undergo tumor biopsy d1, then are vaccinated days 1, 8, and 15 with a multipeptide vaccine. A biopsy day 22 provides information on the effect of vaccination alone on T cell infiltration into tumor. IFNg (up to 2 million units) is injected into at least 1 metastasis, which is biopsied day 24. Additional vaccines are given days 24, 43, and 64. Primary goals are to determine the safety of intratumoral interferon gamma (IFNg) plus a multipeptide melanoma vaccine, and to evaluate the biological effects of vaccine plus IFN-g at the tumor site, to include expression of CXCR3 ligands (CXCL9, CXCL10 & CXCL11) and the magnitude of infiltration of CD8+ CXCR3+ T cells and vaccine-specific T cells. Secondary goals include evaluating effects of vaccine on CXCR3 expression by circulating antigen-experienced CD4 and CD8 T cells, estimating the effects of vaccine plus IFNg on changes in the percentage of FoxP3+ CD25hi CD4+(putative regulatory T cells, Tregs) among tumor infiltrating T cells and to obtain preliminary data on the clinical response of cutaneous or subcutaneous metastases of melanoma to the proposed combination regimen. Clinical trial information: NCT00977145.

Immune responsiveness in a mouse model of combined adoptive immunotherapy with NK and dendritic cells

To determine the tumoricidal ability of combined immunotherapy of natural killer (NK) cells and dendritic cells (DCs) in a melanoma mouse model and the functions of tumor-associated effector cells. A C57BL/6 mouse model of subcutaneous melanoma and lung metastasis was established. NK cells and DCs were cultured and labeled in vitro. Varying frequencies of both NK cells and DCs were adoptively transferred into tumor-bearing mice. Tumor, liver, spleen, and lung were studied for the number and distribution of effector cells. Additionally, CD8+T cell numbers in the lung and numbers of metastatic lung nodules were determined. Co-culture of NK cells and DCs might maintain and promote NK cell activity without exogenous cytokines. Both NK cells and DCs were distributed in the tumor microcirculation and parenchyma. We found significant time-dependent differences in the numbers of infiltrating NK cells and DCs (P < 0.01), which stimulated the highest frequencies of effector cells 4 h after transfer and the lowest at 12 h. Low NK cell numbers were found in the spleen, and fewer numbers were found in liver and lung. Infiltration of tumors with effector cells was greatest following mixed cell transfers as compared to single transfers, and markedly increased CD8+T cells were associated with significant decreases in lung metastases. NK cells and DCs adoptive immunotherapy targeted the tumor and exhibited improved therapeutic efficacy as compared to that of the cells given alone. This strategy could induce tumorigenic immunological memory and suggests that mixed NK cells and DCs adoptive immunotherapy offers therapeutic options against cancer.

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.

Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream

There are limited treatment options for metastatic melanoma, which is almost universally fatal. We report the successful treatment of 64 of 64 cutaneous and subcutaneous melanoma metastases in three patients using high-dose (22 million units per 1.2 ml) intralesional interleukin 2 (IL-2) in combination with topical imiquimod and a retinoid cream. Before intralesional therapy, all patients had been treated surgically and were no longer considered surgical candidates. Rebiopsy of 15 of the treatment sites and long-term follow-up (10, 12, and 27 months) showed regression of all treated tumors. Six months after discontinuation of therapy, one patient developed multiple new cutaneous metastases, but these were also responsive to treatment with intralesional therapy. The other two patients did not experience recurrence of their cutaneous melanoma. However, one of the two patients developed lymph node and brain metastases 18 months after initiation of intralesional therapy, but is still alive, now at 27 months. The concentration of IL-2 used for the intralesional therapy was much higher than in previously reported cases, which may explain the excellent responses that were observed. These results support intralesional high-dose IL-2 as a very effective therapy for controlling cutaneous metastatic melanoma. Additional studies are needed to determine whether this therapy is associated with a survival benefit.

Electrochemotherapy of Cutaneous Metastases of Melanoma-A Case Series Study and Systematic Review of the Evidence

Electrochemotherapy (ECT) is a novel therapeutic option for the treatment of cutaneous and subcutaneous metastases of malignant melanoma. During the treatment, electric pulses are applied to tumor nodules to deliver nonpermeant or poorly permeant chemotherapeutic agents into the cells, increasing local cytotoxicity of anticancer drugs. We compared the clinical effectiveness of ECT as an alternative palliative treatment option for unresectable metastatic lesions of malignant melanoma with a systematic review of reported outcomes. One hundred fifty-eight cutaneous and subcutaneous metastases of nine patients were treated with ECT. All treatments were performed under general anesthesia using intravenous bleomycin injection. Median follow-up was 195 days. In our case series, complete response rate was 23%, and partial response rate was 39%. We observed no change in 30% and progressive disease in 8% of cases. ECT is a simple and effective treatment of single or multiple cutaneous and subcutaneous metastases of melanoma with minimal side effects. Our results provide further data for the growing body of evidence in recently published studies that ECT used for palliation has clinical benefit. The authors have indicated no significant interest with commercial supporters.

Electrochemotherapy of melanoma cutaneous metastases

Electrochemotherapy is an effective treatment of cutaneous and subcutaneous metastases in patients with malignant melanoma. During the treatment, electric pulses are applied to tumor nodules to deliver non-permeating or poorly permeating chemotherapeutic agents into the cells thereby increasing local cytotoxicity of anticancer drugs. In 7 patients 81 cutaneous and subcutaneous melanoma metastases were treated with electrochemotherapy. All treatments were performed under general anesthesia using intravenous bleomycin injection. Median follow-up was 218 days. Complete response rate was 25%, partial response rate was 43%. We observed no change in 26%, and progressive disease in 6%. Electrochemotherapy is a simple and effective treatment of single or multiple cutaneous and subcutaneous metastases of melanoma, with minimal side effects. Our results confirm the results of recently published studies that the treatment used for palliation has clinical benefit and impact on the quality of life.

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.

Complete remission of cutaneous and subcutaneous melanoma metastases of the scalp with imiquimod therapy

Multiple cutaneous and subcutaneous melanoma metastases represent a therapeutic challenge. A 63-year-old man presented with multiple cutaneous and subcutaneous melanoma metastases on his right parieto-occipital region that appeared ten weeks after surgical excision of the primary tumor. Staging showed no further metastases. Because of the large area of cutaneous metastatic spread, the location and the limited possibility of a complete excision, we decided to begin immunomodulatory therapy with imiquimod applied for eight hours daily five days a week. After six weeks of imiquimod monotherapy, a partial remission of the cutaneous metastases had occurred. After 17 months, the remission of these metastases was complete. Four months later the patient is still free of cutaneous, visceral, cerebral and lymph node metastases.

Progress of multiple cutaneous and subcutaneous melanoma metastases of the face during imiquimod treatment

A 68-year-old man developed a local recurrence with multiple cutaneous and subcutaneous nodules three months after excision of a primary malignant melanoma of the temple. Despite extensive surgery and adjuvant irradiation, another local recurrence occurred. Following further local progression during dacarbazine chemotherapy, topical treatment with imiquimod was begun and the chemotherapy was changed to fotemustine. During this treatment further local progression occurred and two months later regional lymph node and distant metastasis were detected. The patient died from his tumor disease eighteen months after the first diagnosis of malignant melanoma.

Preliminary results of an open-label phase I pharmacokinetic/pharmacodynamic study of JNJ26481585: Early evidence of antitumor activity

e13504 Background: JNJ26481585 is a novel orally active pan-histone deacetylase inhibitor (HDACI) which showed potent antitumor efficacy in a wide range of animal tumor models. Methods: A 2-stage accelerated titration design Phase I trial was conducted to characterize safety, establish the maximum tolerated dose (MTD) and determine pharmacokinetics in patients (pts) with refractory solid tumors, of performance status &lt;2 and with adequate hematologic, renal, hepatic and cardiac function. The drug was administered orally, once daily in 3 weekly cycles. Results: To date, 9 pts (median age 59; range 32–74) have been treated at 4 dose levels (DL): 2 (2 pts), 4 (2 pts), 8 (3 pts), and 12 (2 pts) mg. The median number of cycles administered was 2 (range 1–9). Dose-limiting toxicity was seen at 12mg (CTCAE Grade [G] 3 non-sustained ventricular tachycardia [VT] [1 pt] and G3 fatigue [1 pt]) and the 8mg cohort is being expanded. Other toxicity observed at 12mg comprised G2 palpitations with QT prolongation (1 pt), G2 anorexia (1 pt), G2 vomiting (1 pt) and G2 dysgeusia (1 pt). At 8mg, 1 pt on warfarin developed a G2 INR increase. Non-specific ECG changes were observed from the 2mg DL onwards. The drug was generally well tolerated up to 8mg. Exposure to JNJ26481585 increased proportionally over the 2 to 12mg dose range, with a constant metabolite/parent ratio (3.5 for Cmax; 7 for AUC). Two partial responses (PR) and one stable disease (SD) have been observed. PR occurred in 2 pts with metastatic melanoma treated at 12mg : one pt had a PR in visceral and complete response in subcutaneous melanoma metastases after 22 days of drug and has ongoing response 5 months after stopping treatment; the second pt had PR in lymph nodes and reduction of cutaneous lesions of melanoma. One non small cell lung cancer pt treated at 4mg showed SD for 9 cycles. Assessment of histone acetylation as a pharmacodynamic biomarker in peripheral blood lymphocytes and hair follicles is ongoing. Conclusions: JNJ26481585 is generally well tolerated at doses up to 8mg daily. Evidence of promising antitumor activity has been observed with 2 PR to date in patients with metastatic melanoma. The 8mg cohort is being expanded with increased cardiac monitoring. Other schedules may be explored in the future. [Table: see text]

Phase 1 Evaluation of Intralesionally Injected TLR9-agonist PF-3512676 in Patients With Basal Cell Carcinoma or Metastatic Melanoma

Synthetic oligodeoxynucleotides (ODNs), such as PF-3512676, that contain unmethylated cytosine-guanine motifs (CpG ODN) have been identified as highly potent immune activators by in vitro examinations and in murine models. CpG ODNs induce innate and adaptive immune responses by triggering Toll-like receptor 9 expressed by human B cells and plasmacytoid dendritic cells. A phase 1 study was initiated to investigate safety, tolerability, serum cytokine levels, cellular immune responses, and clinical activity of intralesional treatment with PF-3512676 in patients with basal cell carcinoma (BCC) or cutaneous or subcutaneous melanoma metastases. Intrapatient escalating doses of PF-3512676 (up to 10 mg) were injected intralesionally every 14 days in 5 patients with BCC and in cutaneous or subcutaneous metastases of 5 patients with melanoma. PF-3512676 was well tolerated. Local swelling and erythema occurred at the injection site in 9/10 patients. There was only 1 incidence of a grade III hematologic adverse event (lymphocytopenia). Local tumor regressions were observed in patients with BCC (1 complete regression, 4 partial regressions) and metastatic melanoma (1 complete regression). After treatment with PF-3512676, interleukin-6 was increased in all patients, interferon-gamma induced protein-10 in 8/10 patients, interleukin-12p40 in 7/10 patients, and tumor necrosis factor-alpha levels in 6/10 patients. All patients had biopsies; moderate to abundant cellular infiltrates of lymphocytes were found posttreatment in most lesions of both histologic types. Intralesional treatment of skin tumors with PF-3512676 was safe and well tolerated. Despite the relatively low dosage, clinical activity was demonstrated both in patients with BCC and with cutaneous or subcutaneous metastatic melanoma lesions.

Long lasting complete response in melanoma treated by electrochemotherapy

The optimal treatment of multiple cutaneous and subcutaneous metastases of melanoma still remains unresolved. There are many different possible treatment modalities. We present a case of melanoma on the calf in which multiple cutaneous and subcutaneous metastases were treated by electrochemotherapy with cisplatin. They completely responded for eight years. After eight years two new metastatic nodules occurred and were treated by electrochemotherapy with cisplatin and again complete response was achieved. The case presents the advantages of electrochemotherapy of multiple cutaneous and subcutaneous metastases of melanoma, its relative simplicity, its minimal side effects and the possibility to treat recurrent disease as many times as needed, with long lasting complete responses.