Melanoma Brain Metastases in the Era of Target Therapies: An Overview

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed

Reduced-intensity allogeneic hematopoietic stem cell transplantation in metastatic colorectal cancer as a novel adoptive cell therapy approach. The European group for blood and marrow transplantation experience

Abstract Reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (HCT) allowed the existence of an allogeneic cell-mediated antitumor effect in metastatic colorectal cancer (mCRC) to be explored. We report on 39 patients with progressing mCRC treated with different RIC regimens in a multicenter clinical trial of the European Bone Marrow Transplantation Group. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (15%), and partial response (PR) in 2 (5%). All patients engrafted (median donor T cell chimerism of 90% at day +60). Transplant-related morbidities were limited. Grades II-IV acute graft-versus-host disease (aGVHD) occurred in 14 patients (35%) and chronic GVHD (cGVHD) in 9 patients (23%). Transplant-related mortality occurred in 4 patients (10%). The best tumor responses were: 1 complete response (CR) (2%), 7 PR (18 %), and 10 SD (26%), giving an overall disease control in 18 of 39 patients (46%). Allogeneic HCT after RIC is feasible; the collected results compared favorably in terms of tumor response with those observed using conventional approaches beyond second-line therapies. The study of an allogeneic cell based therapy in less advanced patients is warranted

Post-Transplant Cyclophosphamide and Tacrolimus–Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors

Abstract Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571

HSCT with Mismatched Unrelated Donors (MMUD): A Comparison of Different Platforms for GvHD Prophylaxis

HSCT from an unrelated HLA-mismatched donor (MMUD) is one of the alternatives where an HLA-matched donor is not found. The aim of this study was to compare GvHD prophylaxis with anti-thymocyte globulin (ATG) vs. post-transplant cyclophosphamide (PT-Cy). Thirty-nine adult patients were uniformly treated with rabbit ATG-Cy-A-MTX and peripheral blood stem cell (PBSC) and 40 adult patients with PT-Cy-MMF-tacrolimus and PBSC. This retrospective study was registered at ClinicalTrials.gov NCT04598789. Three-year overall survival was 42% vs. 64% for ATG and PT-Cy (p p = 0.0033) and the three-year relapse incidence (RI) was 15% vs. 28% (p = NS), respectively. The incidences of day-100 GvHD graded II–IV and III–IV were 39% vs. 7% (p = 0.0006) and 11% vs. 0% (p = 0.04), respectively, whereas the three-year cGvHD incidences were 48% vs. 13% (p = 0.0005), respectively. We were able to show how PT-Cy can reduce the incidence of GvHDs and TRM in adults, but relapse remains an issue

Interaction between Shiga Toxin and Monoclonal Antibodies: Binding Characteristics and in Vitro Neutralizing Abilities

toxin