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• Chimeric antigen receptor T therapy for solid tumors has encountered challenges in early clinical trials. • Toxicity, antigen targeting, trafficking, and immune evasion hamper cell activity. • Novel techniques are being explored to improve treatment safety and efficacy. Immune effector cell (IEC) therapy is emerging as a promising approach in the field of cancer immunotherapy. Clinical IEC trials, predominantly using chimeric antigen receptor (CAR) T cells, have shown excellent responses in CD19+ B cell malignancies and multiple myeloma. In solid tumors, preclinical data are encouraging, but clinical data are in their infancy, and there are challenges in using CAR T therapy in this setting, including (1) on-target off-tumor toxicity, (2) optimal target identification, (3) effective trafficking into bulky tumor tissue, and (4) resistance to tumor immune evasion mechanisms. Novel techniques and modifications are being explored in both the preclinical and clinical settings, aiming to improve treatment efficacy and address the aforementioned obstacles to successful CAR T therapy in solid tumors. Here we review these challenges in a clinically oriented approach and summarize published clinical trials using CAR T therapy in a variety of solid tumors. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Highlights • cGVHD remains a serious complication of cell transplantation. • Available options on SR-cGVHD vary in both cost and effectiveness. • Attention to economic issues when treating SR-cGVHD can help guide how treatments should be sequenced. Abstract Given the increasing incidence of chronic graft-versus-host disease (cGVHD) and its rapidly escalating costs due to many lines of drug treatments, we aimed to perform a meta-analysis to assess the comparative effectiveness of various treatment options. Using these results, we then conducted a cost-effectiveness analysis for the frequently utilized agents in steroid-refractory cGVHD. We searched for studies examining tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, extracorporeal photopheresis, pomalidomide, and methotrexate. Studies with a median follow-up period shorter than 6 months and enrolling fewer than 5 patients were excluded. Meta-analysis for overall and organ system–specific GVHD response (overall response [ORR], complete response [CR], and partial response [PR]) was conducted for each intervention. Cost per CR and cost per CR + PR were calculated as the quotient of the 6-month direct treatment cost by CR and CR + PR. Forty-one studies involving 1047 patients were included. CR rates ranged from 7% to 30% with rituximab and methotrexate, respectively, and ORR ranged from 30% to 85% with tacrolimus and ruxolitinib, respectively. Cost per CR ranged from US$1,187,657 with ruxolitinib to US$680 with methotrexate. Cost per ORR ranged from US$453 for methotrexate to US$242,236 for ibrutinib. The most cost-effective strategy was methotrexate for all of the organ systems. Pomalidomide was found to be the least cost-effective treatment for eye, gastrointestinal, fascia/joint, skin, and oral GVHD, and imatinib was found to be the least cost-effective treatment for liver and extracorporeal photopheresis for lung GVHD. We observed huge cost-effectiveness differences among available agents. Attention to economic issues when treating cGVHD is important to recommend how treatments should be sequenced, knowing that many patients will cycle through available agents. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first-line treatment; however, less than one-half of patients achieve durable remission. Studies suggest that TNF-α, a cytokine released from the bone marrow during conditioning, is involved in the pathogenesis of aGVHD. We retrospectively evaluated the outcome of anti-TNF-α therapy with infliximab in 35 patients with steroid refractory (SR) aGVHD. Infliximab was administered intravenously at 10 mg/kg for a median of 4 doses (range, 1 to 6) on a weekly basis. The overall response rates were 40% (17% complete response [CR], 23% partial response [PR]) at 4 weeks, 23% (9% CR, 14% PR) at 8 weeks, and 17% (all CR) at 12 weeks. Twenty-nine (83%) patients had infectious complications within 12 weeks of initiation of infliximab. These infections included 40 bacterial infections, 6 invasive fungal infections, and 5 viral reactivations. Twelve patients (34%) died secondary to infections. Overall survival at 12 weeks and 6 months from the start of infliximab therapy was 37% (13 of 35) and 17% (6 of 35), respectively; with most deaths secondary to complications from GVHD and infections. In conclusion; the use of infliximab therapy in patients with SR-aGVHD is associated with a modest poorly sustained response along with a heightened risk of severe infections. Future studies with more effective and less toxic therapies are needed for these patients. [ABSTRACT FROM AUTHOR]

Strategies for mobilization and collection of peripheral blood stem cells (PBSC) for autologous hematopoietic stem cell transplant (auto-HCT) include growth factors (GF) such as filgrastim, either alone or with chemokine receptor antagonist plerixafor, or filgrastim/plerixafor in combination with chemotherapy (GF + chemo). In this single center retrospective analysis, we compared PBSC mobilization with GF only (filgrastim +/- plerixafor) to GF + chemo. Chemotherapy used was cyclophosphamide alone, or modified CVAD. Primary endpoints were engraftment, transfusion requirement, duration of hospitalization, NRM, PFS and OS. We identified 1361 patients who had auto-HCT between 1988 and 2015; 1137 with GF only and 224 with GF + chemo. As shown in Table 1, more patients in the GF + chemo group had high-risk cytogenetics (25.6 vs 20.3%), lower ≥VGPR rate to induction (20 vs 50%), and required more intense conditioning (25 vs 13%). Additionally, patients with GF + chemo collected target PBSC in fewer days (2 vs. 3), received a higher CD34+ cell dose (5.6 vs. 4.1) with no difference in neutrophil or platelet engraftment, had longer hospitalization post auto-HCT (19 vs 17 days), and required more PRBC transfusions (2 vs 1), Table 2. The 100-day NRM was <1% in both groups (p=0.712). With a median follow up of 75.3 months, both PFS (HR=1.44 CI:1.22-1.69, p<0.001) and OS (HR=1.30 CI: 1.06-1.60, p=0.013) were significantly shorter in GF + chemo group. On multivariable Cox analysis, GF + chemo, older age, ISS stage III, high-risk cytogenetics and progressive disease after induction were associated with shorter PFS. There was no statistically significant difference between GF only or GF + chemo in engraftment or NRM. The shorter survival in the GF + chemo group may be attributed to a higher proportion of poor-risk patients in that group. [ABSTRACT FROM AUTHOR]