Mega-dose 90Y-Ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCL), though outcomes are worse in aggressive disease and most patients will still experience relapse. Radioimmunotherapy (RIT) using 90Y-Ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that mega-doses of 90Y-Ibritumomab tiuxetan with reduced-intensity conditioning (RIC) could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-Ibritumomab tiuxetan (1.5mCi/kg, maximum 120mCi), fludarabine, then 2Gy total body irradiation (TBI) prior to HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y activity of 113.6 mCi (range 71.2-129.2) was administered delivering a median of 552cGy to liver (range 499-2411cGy). The estimated 1 and 5-year PFS was 55% (95% CI, 31-73%) and 50% (95% CI, 27-69%) with a median PFS of 1.57 years. The estimated 1- and 5-year overall survival (OS) was 80% (95% CI, 54-92%) and 63% (95% CI, 38-81%) with a median OS of 6.45 years. Sixteen patients (80%) experienced grade ≥3 toxicities, although nonrelapse mortality was 10% at 1-year. No patients developed secondary AML/MDS. Mega-dose 90Y-Ibritumomab tiuxetan, fludarabine, and low-dose TBI followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified endpoint while producing nonhematologic toxicities comparable to standard RIC regimens. (Registered at ClinicalTrials.gov as NCT01434472).

Local Destruction of Tumors and Systemic Immune Effects

Current immune-based therapies signify a major advancement in cancer therapy; yet, they are not effective in the majority of patients. Physically based local destruction techniques have been shown to induce immunologic effects and are increasingly used in order to improve the outcome of immunotherapies. The various local destruction methods have different modes of action and there is considerable variation between the different techniques with respect to the ability and frequency to create a systemic anti-tumor immunologic effect. Since the abscopal effect is considered to be the best indicator of a relevant immunologic effect, the present review focused on the tissue changes associated with this effect in order to find determinants for a strong immunologic response, both when local destruction is used alone and combined with immunotherapy. In addition to the T cell-inflammation that was induced by all methods, the analysis indicated that it was important for an optimal outcome that the released antigens were not destroyed, tumor cell death was necrotic and tumor tissue perfusion was at least partially preserved allowing for antigen presentation, immune cell trafficking and reduction of hypoxia. Local treatment with controlled low level hyperthermia met these requisites and was especially prone to result in abscopal immune activity on its own.

Immunologic Effect of Polysaccharides Extracted from Sipunculus nudus (SNP) on Hepatoma HepG2-bearing Mice

Since many studies have clarified the biological activity of polysaccharides, we investigated the effect of SNP which was the water-soluble polysaccharides extracted from Sipunculus nudus on Hepatoma HepG2-bearing Mice to verify the potential of SNP as an effective clinical agent for liver cancer therapy. SNP were administered at the doses of 50,100, and 200 mg/kg to HepG2-bearing mice to determine their antitumor effects. SNP had an inhibitory effect on the growth of HepG2 cells and enhanced the immunological effect on HepG2 tumor-bearing mice. SNP increased the expression of IL-2, IFN-γ, and TNF-α cytokines in serum, suggesting that SNP can strengthen the antitumor immune response. In addition, SNP increased ATF4, DDIT3, and IkBα expression and decreased CYR61, HSP90, and VEGF expression, all of which are proteins involved in antitumor activity and cell death/survival. our results suggested that SNP may be a novel antitumor agent.Summary statementSNP(polysaccharides extracted from Sipunculus nudus) mediates anti-tumor activity through influencing immunoregulation, and SNP can be explored as a promising candidate for future anticancer drug.

Feasibility study of multiple HLA-class IA restricted peptide vaccines (KRM-19) for metastatic triple negative breast cancer (TNBC).

164 Background: Our previous phase II clinical trial has indicated that the therapeutic selected personalized peptide vaccines (PPV) were effective for boosting anticancer immunity and the immune response after PPV was associated with the clinical outcome as a prognostic factor for metastatic breast cancer (mBC). Based on the data from the PPV studies, we have conducted an early phase II study to evaluate the safety and the efficacy of a new regimen using multiple peptide vaccines (KRM-19) for pts with metastatic TNBC. Methods: KRM-19 consisted of 19 mixed peptides which were chosen from the previously reported 31 PPVs according to their anti-tumor immunologic effect and safety profile for mBC pts. All patients had histologically confirmed measurable ER-PgR-Her2- mBC and their human leukocyte antigen (HLA)-A molecules should be each of -A2, A3, A11, A24, A26, A31, or A33. KRM-19 (19mg/ml) was administrated subcutaneously in order with schedule of every week for a total of 6 doses. The concurrent conventional chemo- and/or endocrine therapy was not permitted for the combination, but was available for post-study treatment. Measurement of peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses were conducted before and after vaccination. Levels of IgG reactive to each of the 19 peptides in the pre- and post-vaccination plasma were measured using the LUMINEX system at every 6 vaccinations. Peptide-specific CTL responses were examined by INF-ɤ ELISPOT. Clinical response was evaluated by RECIST criteria. Results: 10 patients with refractory metastatic TNBC received all 6 vaccines and 10/10 patients experienced Grade 1-2 skin reaction at injection site, 5/10 pts had Grade 2-3 liver function disorder, 3/10 and 1/10 pts had Grade 2 bone marrow suppression and nausea, respectively. The clinical responses were assessed in 8 pts included 1 PR case, 4 SD cases, and 3 PD cases. The evaluation of other clinical and immunologic data is underway. Conclusions: Subcutaneous KRM-19 vaccine administration was safe and resulted in a 12.5% objective response and 62.5% clinical benefit rate in TNBC pts, warranting further larger scale study. Clinical trial information: UMIN000014616.

Oxaliplatin Induced Digital Ischemia and Necrosis

Introduction. Digital ischemia is a rare complication of several chemotherapeutic medications. We aimed to present a patient with digital ischemia, secondary to a new generation chemotherapeutic drug, oxaliplatin.Case Report. 62-year-old woman presented to our department with severe pain, paresthesia, and distal acrocyanosis on her right hand fingertips. Her complaints started five days after the third cycle of a chemotherapy protocol consisting of 5-fluorourasil (5-FU), folinic acid, and oxaliplatin due to advanced colon carcinoma. On physical examination, hemorrhagic and partly ulcerative lesions were detected at her right hand fingertips. Radial and ulnar pulses were absent at affected side. Digital subtraction angiography revealed severe vascular resistance in the affected extremity. Iloprost trometamol treatment was started with the dosage of 1 ng/kg/min. In addition, low-molecule-weight heparin was used for preventing possible microemboli. Symptomatic relief was provided after five days, and patient was discharged on 7th day of treatment.Discussion. The pathogenesis of oxaliplatin induced vascular toxicity remains unclear. Endothelial damage, increased adherence of platelets, deposition of immune complexes as an immunologic effect of oxaliplatin, and hypercoagulable state may be the reason for arterial thrombosis, digital microemboli, possible digital ischemia, and their several consequences.