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Abstract: Active immunization of follicular lymphoma patients with idiotypic vaccines elicits antigen-specific antibody responses, T-cell responses, and antitumor effects. We hypothesized that these vaccinated patients could generate tumor-specific immune responses, not only against idiotype, but also against other tumor-associated antigens (TAA) by a mechanism of epitope spreading. To identify potential antigens, a phage surface expressed cDNA library derived from primary tumor cells was screened with sera from idiotype-vaccinated patients. Consistent with our hypothesis, we identified two immunogenic peptides (FL-aa-7 and 18), unrelated to idiotype, which were recognized by postvaccine sera but not by prevaccine or normal human sera. These peptide sequences derived from the 5′-untranslated regions of the human GTPase, IMAP family member 7 gene (FL-aa-7) and an alternative reading frame of U1-snRNP 70 (FL-aa-18), respectively, suggesting that epitope spreading had occurred. [Copyright &y& Elsevier]

The role of B cells in T-cell priming is unclear, and the effects of B-cell depletion on immune responses to cancer vaccines are unknown. Although results from some mouse models suggest that B cells may inhibit induction of T cell–dependent immunity by competing with antigen-presenting cells for antigens, skewing T helper response toward a T helper 2 profile and/or inducing T-cell tolerance, results from others suggest that B cells are necessary for priming as well as generation of T-cell memory. We assessed immune responses to a well-characterized idiotype vaccine in individuals with severe B-cell depletion but normal T cells after CD20-specific antibody–based chemotherapy of mantle cell lymphoma in first remission. Humoral antigen- and tumor-specific responses were detectable but delayed, and they correlated with peripheral blood B-cell recovery. In contrast, vigorous CD4+ and CD8+ antitumor type I T-cell cytokine responses were induced in most individuals in the absence of circulating B cells. Analysis of relapsing tumors showed no mutations or change in expression of target antigen to explain escape from therapy. These results show that severe B-cell depletion does not impair T-cell priming in humans. Based on these results, it is justifiable to administer vaccines in the setting of B-cell depletion; however, vaccine boosts after B-cell recovery may be necessary for optimal humoral responses. [ABSTRACT FROM AUTHOR]

B-cell malignancy-derived Ig may be considered a model tumor antigen for vaccine development. However, as a non-immunogenic self antigen, it must also be first rendered immunogenic by chemical or genetic fusion to carriers which enable the induction of protective antitumor immunity in murine tumor models. Our group has demonstrated that active immunizations of human patients with idiotypic vaccines elicited antigen-specific CD8[sup+] T-cell responses and antitumor effects. Several alternative preclinical strategies to develop vaccines have been previously reported, including fusion of tumor idiotype-derived single chain Fv with cytokines and immunogenic peptides. On the other hand, we have recently explored a different approach in which the model antigen is rendered immunogenic in mice by genetically fusing it to a chemokine moiety. Administration of these vaccines as fusion proteins or naked DNA vaccines may allow efficient targeting of antigen-presenting cells in vivo. Potent antitumor immunity was dependent on the generation of specific anti-idiotypic antibodies and both CD4[sup+] and CD8[sup+] effector T cells. We propose that chemoline fusion may represent a novel, general strategy for formulating existing or newly identified tumor and HIV antigens into vaccines for cancer and AIDS, respectively, which elicit potent CD8[sup+] T-cell immunity. [ABSTRACT FROM AUTHOR]

Examines the effect of vaccination with the idiotype of immunoglobulin expressed by a B-cell malignancy (Id) combined with granulocyte colony-stimulating factor. Enhanced protective antitumor immunity from this immunization; Factors behind this effect; Mediation of this effect from the enhancement of T-cell immunity.

Presents results which demonstrate that the autologous immunoglobulin idiotype can be formulated into an immunogenic, tumor-specific antigen in humans with B-cell lymphoma. Implications for large-scale trials of active specific immunotherapy of this disease; Toxicity associated with the vaccine; More.

Examines the importance of dendritic cells to immunize against tumor antigens in improving the prospects for cancer vaccines. Two approaches to harnessing dendritic cells antitumor response; Immunization of mice with tumor RNA transfected dendritic cells; Issues related to the selection of candidate tumor antigens.

The authors comment on the results of a multicenter phase II study wherein patients with castration-resistant metastatic prostate cancer received the standard three doses of sipuleucel to determine changes in immune cell infiltrates in the paired tumor tissues. They describe the amount of infiltrating T cells found and the limitations of the study. They also discuss the implications of the study for the mechanism of action of sipuleucel-T.

The article presents the suggestion on how to change investment in translational science by academic medical centers. Topics inlcude the institution's prestige has been based on the reputation, innovation, and deep research and clinical expertise of its faculty, the large portion of basic research has been funded through federal agencies, and the crucial characteristics of programs has structured to support late preclinical product development.

The clonotypic surface Ig receptor expressed by malignant B cells,idiotype,is a tumor-specific antigen and an attractive target for active immunotherapy.While Ab's specific for tumor idiotype have been well described in patients with B cell malignancies,the precise antigenic epitopes in human idiotype recognized by autologous T cells remain largely unknown.We report here that T cell lines generated from lymphoma patients actively immunized with idiotype protein specifically recognized multiple,unique immunodominant epitopes in autologous tumor idiotype.Synthetic peptides corresponding to hypervariable,but not frame- work,regions of Ig heavy chain specifically stimulated CD4 +and CD8 +T cells to proliferate and secrete proinf lammatory cytokines in an MHC-associated manner.Detailed analysis revealed a minimal determi- nant of an immunodominant epitope,comprising critical residues at the amino terminus that may be a prod- uct of somatic hypermutation.Association of idiotype-specific T cell responses with previously documented molecular remissions in idiotype-vaccinated patients suggests that the newly identified T cell epitopes may be clinically relevant.Such antigenic epitopes may serve as candidates for novel peptide-vaccine strategies,and as tools to selectively expand tumor antigen --specific T cells for adoptive immunotherapy and for monitoring T cell immunity in vaccinated patients. [ABSTRACT FROM AUTHOR]

The clonotypic surface Ig receptor expressed by malignant B cells, idiotype, is a tumor-specific antigen and an attractive target for active immunotherapy. While Ab's specific for tumor idiotype have been well described in patients with B cell malignancies, the precise antigenic epitopes in human idiotype recognized by autologous T cells remain largely unknown. We report here that T cell lines generated from lymphoma patients actively immunized with idiotype protein specifically recognized multiple, unique immunodominant epitopes in autologous tumor idiotype. Synthetic peptides corresponding to hypervariable, but not framework, regions of Ig heavy chain specifically stimulated CD4(+) and CD8(+) T cells to proliferate and secrete proinflammatory cytokines in an MHC-associated manner. Detailed analysis revealed a minimal determinant of an immunodominant epitope, comprising critical residues at the amino terminus that may be a product of somatic hypermutation. Association of idiotype-specific T cell responses with previously documented molecular remissions in idiotype-vaccinated patients suggests that the newly identified T cell epitopes may be clinically relevant. Such antigenic epitopes may serve as candidates for novel peptide-vaccine strategies, and as tools to selectively expand tumor antigen-specific T cells for adoptive immunotherapy and for monitoring T cell immunity in vaccinated patients. [ABSTRACT FROM AUTHOR]

In vitro priming of T cells with dendritic cells (DC) pulsed with clinically relevant, but weak antigens such as tumor idiotype (Id), is an attractive strategy to generate tumor-specific T lymphocytes. In order to enhance the specific antitumor effect of allogeneic stem cell grafts, we investigated whether induction of tumor specific T cells using autologous DC pulsed with patient's myeloma Id could be maintained and potentiated by in vitro priming. For induction of T cells, DC (5 × 10[sup 5]/well) were cultured with autologous nonadherent cells (DONA) (5 × 10[sup 6]/well) and antigen (TT10 ug/ml, KLH 100 ug/ml and Id 100 ug/ml). The T cells were restimulated every 8-10 days with the corresponding antigen and autologous DC. After 2-4 cycles of in vitro priming, the T cells were compared with nonadherent cells obtained after 2 h attachment on day 0 (DoNA) for antigen-specific cytokine production. In vitro primed T cells (2-4 cycles of stimulation with Ag and DC) showed significant antigen-specific cytokine responses (IFN-γ, TNF-α, GM-CSF) to TT. Similarly, in vitro priming of T cells to Id-pulsed DC resulted in marked increases in cytokine production for both myeloma Id proteins tested. These data suggest that multiple in vitro immunization using DC could be beneficial in generating tumor specific T cells from normal donor PBMC, which may be used for adoptive immunotherapy (e.g. "tumor-specific" donor lymphocyte infusion) of B cell malignancies. In vitro immunization may also offer an alternative to immunization of healthy stem cell transplant donors with tumor antigen. [ABSTRACT FROM AUTHOR]

Mammalian defensins are small, cationic, antimicrobial peptides encoded by the host that are considered to be important antibiotic-like effectors of innate immunity. By using chemokine receptors on dendritic cells and T cells, defensins might also contribute to the regulation of host adaptive immunity against microbial invasion. Defensins have considerable immunological adjuvant activity and linkage of β-defensins or selected chemokines to an idiotypic lymphoma antigen has yielded potent antitumor vaccines. The functional overlap between defensins and chemokines is reinforced by reports that some chemokines have antimicrobial activities. Although showing similarity in activity and overall tertiary structure, the evolutionary relationship between defensins and chemokines remains to be determined. [Copyright &y& Elsevier]

B-cell malignancies can potentially be cured by CD19 chimeric antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL. [ABSTRACT FROM AUTHOR]

Summary: In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well‐tolerated in previously untreated patients with advanced‐stage, indolent non‐Hodgkin lymphoma (iNHL). After a median patient follow‐up of more than 108 months, we performed an intent‐to‐treat analysis of our 83 participants. Progression‐free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten‐year PFS rates for those with beta‐2‐microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10‐year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long‐term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10‐year follow‐up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with an immune suppressive phenotype. They represent a critical component of the immune suppressive niche described in cancer, where they support immune escape and tumor progression through direct effects on both the innate and adaptive immune responses, largely by contributing to maintenance of a high oxidative stress environment. The number of MDSCs positively correlates with protumoral activity, and often diminishes the effectiveness of immunotherapies, which is particularly problematic with the emergence of personalized medicine. Approaches targeting MDSCs showed promising results in preclinical studies and are under active investigation in clinical trials in combination with various immune checkpoint inhibitors. In this review, we discuss MDSC targets and therapeutic approaches targeting MDSC that have the aim of enhancing the existing tumor therapies. [ABSTRACT FROM AUTHOR]

Background: Although the outcomes of patients with mantle cell lymphoma (MCL) have improved, there is still no cure. Bortezomib has a 33% response rate in relapsed/refractory MCL and has shown additive and/or synergistic effects in preclinical trials with known effective agents.Methods: This is a report of a prospective phase 2 trial of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD)/rituximab, high-dose methotrexate, and high-dose cytarabine (BzR-MA) for 95 patients with newly diagnosed MCL.Results: The overall and complete response rates were 100% and 82%, respectively. Hematologic toxicity was high but expected and did not lead to an increased incidence of neutropenic fever or dose reductions in comparison with a similar reported regimen without bortezomib. After a median follow-up of 44 months, the median overall survival had not been reached, and the time to treatment failure (TTF) was 55 months, which is not different from that of historical controls.Conclusions: BzR-hyperCVAD/BzR-MA at the dose and schedule studied produced high rates of response and a TTF similar to that of historical reports without bortezomib. Cancer 2018;124:2561-9. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long-term follow-up results for patients treated with these regimens. We present long-term survival outcomes from a pivotal phase II trial of rituximab, hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R-HCVAD/MA). At 15 years of follow-up (median: 13·4 years), the median failure-free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15-year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10-year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5-12·2%). In patients with newly diagnosed MCL, R-HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one-third of the younger patients (≤65 years). [ABSTRACT FROM AUTHOR]

B cell receptor (BCR) signalling is an important pathway in diffuse large B cell lymphoma (DLBCL). In response to BCR triggering, normal and malignant B cells secrete the chemokines CCL3 and CCL4 to attract accessory cells to the tissue microenvironment. We measured CCL3 and CCL4 serum concentrations in 102 patients with newly diagnosed DLBCL by enzymelinked immunosorbent assay, investigated their prognostic impact and validated our findings in an independent cohort of 51 patient samples. We also tested CCL3 and CCL4 secretion by DLBCL cells, and the influence of BTK inhibitors on the secretion of these chemokines. High CCL3 (≥40 pg/ml) serum concentrations correlated with higher international prognostic index, lactate dehydrogenase and β2 microglobulin, as did CCL4 (≥180 pg/ml) with advanced Ann Arbor stages. High CCL3 levels correlated with significantly shorter progression-free and overall survival. The in vitro studies demonstrated that activated B cell-like, but not germinal centre B cell-like DLBCL cells, secrete high levels of CCL3 and CCL4 after BCR triggering, which was exquisitely sensitive to BCR pathway inhibition. These findings support CCL3 and CCL4 protein concentrations as biomarkers for BCR pathway activation and prognosis in DLBCL. [ABSTRACT FROM AUTHOR]

We conducted a phase II study of the AKT inhibitor, MK2206 in patients with relapsed or refractory lymphoma of any histology excluding Burkitt lymphoma or lymphoblastic lymphoma. MK-2206 was administered orally at 200 mg once weekly in 28-d cycles up to 12 cycles in the absence of progression or significant toxicity. The dose was adjusted based on tolerance. A total of 59 patients were enrolled. The final doses patients received were 300 mg ( n = 33), 250 mg ( n = 2), 200 mg ( n = 16) and 135 mg ( n = 8). Based on intent-to-treat analysis, objective response was observed in 8 (14%) patients (2 complete response and 6 partial response), with median response duration of 5·8 months. The overall response rate was 20% in 25 patients with classical Hodgkin lymphoma. Rash was the most common toxicity (any grade 53%, Grade 3 in 15%) and was observed in a dose-dependent manner. The correlative cytokine analysis showed paradoxical increase in several cytokines, which may be explained by negative feedback mechanism induced by the on-target effect of AKT inhibitor. Our data demonstrate that MK2206 has a favourable safety profile with a modest activity in patients with relapsed Hodgkin lymphoma. The future studies should explore mechanism-based combinations (clinicaltrials.gov NCT01258998). [ABSTRACT FROM AUTHOR]

A phase II study was performed to evaluate the efficacy of hyper-fractionated cyclophosphamide, vincristine, pegylated liposomal doxorubicin and dexamethasone alternating with methotrexate/cytarabine ( HCVIDD/ MA) in patients with newly diagnosed peripheral T-cell lymphoma ( PTCL), excluding ALK-positive anaplastic large cell lymphoma. Fifty-three patients were enrolled. Treatment was planned for up to 8 cycles but only 9% of patients received more than 6 cycles due primarily to disease progression ( n = 13) or prolonged thrombocytopenia ( n = 12). The overall response rate was 66% with a complete response rate of 57%. Median progression-free survival ( PFS) was 7·5 months. With a median follow-up of 7·6 years, 5-year PFS and overall survival ( OS) were 21% and 48%, respectively. The patients with extranodal Natural Killer-cell lymphoma had a shorter PFS (median, 2·4 months) than other subtypes. Grade 3/4 anaemia, neutropenia and thrombocytopenia were observed in 66%, 74% and 79% of patients, respectively. Of note, 23% of patients discontinued therapy due to prolonged thrombocytopenia. In conclusion, HCVIDD/ MA for the first-line treatment of PTCL patients is associated with significant myelosuppression leading to poor treatment adherence, and the response and survival outcomes with this regimen are similar to standard CHOP. This study was registered at as # NCT00290433. [ABSTRACT FROM AUTHOR]

We conducted a prospective phase II trial of pentostatin, cyclophosphamide and rituximab as initial therapy for patients with previously untreated advanced stage low-grade or indolent B-cell lymphomas ( iNHLs). Of 83 evaluable patients, 91·6% attained an overall response and 86·8% a complete or unconfirmed complete response. The 3-year progression-free survival ( PFS) and overall survival rates were 73% and 93%, respectively. The 3-year PFS rate was significantly different for different diagnoses ( P = 0·01): 83% [95% confidence interval ( CI): 0·72, 0·96] for follicular lymphomas, 73% (95% CI: 0·54, 1·0) for marginal zone lymphomas and 61% (95% CI: 0·46, 0·81) for small lymphocytic lymphomas. The most common adverse events were haematological. Of 509 cycles of chemotherapy administered, grade 3 or 4 neutropenia was reported in 68 cycles (13% of cycles administered) and most frequently occurred during cycles 4-6. This is the first report demonstrating the effectiveness of pentostatin, cyclophosphamide and rituximab in patients with previously untreated iNHLs, including those over 60 years of age. [ABSTRACT FROM AUTHOR]

We applied a highly sensitive next-generation sequencing method to identify lymphoma-specific immunoglobulin gene segments in classical Hodgkin lymphoma ( CHL) at initial diagnosis or recurrence, and assessed the ability of detecting such lymphoma-specific sequences in peripheral blood ( PB). Seventeen CHL cases were tested and lymphoma-specific sequences were identified in 12 of the primary tumour biopsies. In 11 of these patients whose paired PB samples were available, tumour-specific clonotypes were detected in PB in eight patients. This data demonstrates the feasibility of detecting circulating tumour-specific sequences, creating an unprecedented opportunity to optimize the future treatment and monitoring strategies for patients with CHL. [ABSTRACT FROM AUTHOR]

Summary Background Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma. Methods In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1–21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m 2 as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov , number NCT00695786 . Findings 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83–95). Complete responses occurred in 65 (63%, 95% CI 53–72) and partial responses in 28 patients (27%, 19–37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]). Interpretation Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study ( NCT01476787 ) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress. Funding Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant. [ABSTRACT FROM AUTHOR]

90Y-ibritumomab-tiuxetan (90 YIT) was used as a first-line therapy for patients with early-stage follicular lymphoma ( FL) or marginal zone B-cell lymphoma ( MZL). Thirty-one patients were treated, with an overall 3-month response rate of 100% (68% complete response, 29% unconfirmed complete response and 3% partial response). At a median follow-up of 56 months, ten patients (32%) had disease relapse or progression. The progression-free rates at 3 and 5 years were lower in males, patients with FL, stage II diseaseand non-bulky disease, although they did not reach statistical significance. Grade 3-4 neutropenia, thrombocytopenia and anaemia were 61%, 35%, and 3%, respectively. 90 YIT was well tolerated, including in those patients over 60 years old, and achieved high response rates in patients with early-stage low-grade B-cell lymphomas. Bulky disease did not adversely affect tumour response. [ABSTRACT FROM AUTHOR]

Abstract: Success of an immunotherapy for cancer often depends on the critical balance of T helper 1 (Th1) and T helper 2 (Th2) responses driven by antigen presenting cells, specifically dendritic cells (DCs). Th1-driven cytotoxic T cell (CTL) responses are key to eliminating tumor cells. It is well established that CpG oligonucleotides (ODN), a widely studied Toll-like receptor 9 (TLR9) agonist, used to enhance Th1 response, also induces high levels of the anti-inflammatory, Th2-promoting cytokine IL10, which could dampen the resulting Th1 response. Biomaterials-based immunomodulatory strategies that can reduce IL10 production while maintaining IL12 levels during CpG delivery could further enhance the Th1/Th2 cytokine balance and improve anti-tumor immune response. Here we report that dual-delivery of IL10-silencing siRNA along with CpG ODN to the same DCs using pathogen-mimicking microparticles (PMPs), significantly enhances their Th1/Th2 cytokine ratio through concurrent inhibition of CpG-induced IL10 production. Co-delivery of poly(I:C), a TLR3 agonist had only minor effects on IL10 levels. Further, simultaneous immunotherapy with CpG ODN and IL10 siRNA enhanced immune protection of an idiotype DNA vaccine in a prophylactic murine model of B cell lymphoma whereas co-delivery of poly(I:C) and CpG did not enhance protection. These results suggest that PMPs can be used to precisely modulate TLR ligand-mediated immune-stimulation in DCs, through co-delivery of cytokine-silencing siRNAs and thereby boost antitumor immunity. [Copyright &y& Elsevier]

90Y‐ibritumomab‐tiuxetan (90YIT) was used as a first‐line therapy for patients with early‐stage follicular lymphoma (FL) or marginal zone B‐cell lymphoma (MZL). Thirty‐one patients were treated, with an overall 3‐month response rate of 100% (68% complete response, 29% unconfirmed complete response and 3% partial response). At a median follow‐up of 56 months, ten patients (32%) had disease relapse or progression. The progression‐free rates at 3 and 5 years were lower in males, patients with FL, stage II diseaseand non‐bulky disease, although they did not reach statistical significance. Grade 3–4 neutropenia, thrombocytopenia and anaemia were 61%, 35%, and 3%, respectively. 90YIT was well tolerated, including in those patients over 60 years old, and achieved high response rates in patients with early‐stage low‐grade B‐cell lymphomas. Bulky disease did not adversely affect tumour response. [ABSTRACT FROM AUTHOR]

Immune evasion is an emerging hallmark of cancer progression. However, functional studies to understand the role of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are limited by the lack of available specific cell surface markers. We adapted a competitive peptide phage display platform to identify candidate peptides binding MDSCs specifically and generated peptide-Fc fusion proteins (peptibodies). In multiple tumor models, intravenous peptibody injection completely depleted blood, splenic and intratumoral MDSCs in tumor-bearing mice without affecting proinflammatory immune cell types, such as dendritic cells. Whereas control Gr-1-specific antibody primarily depleted granulocytic MDSCs, peptibodies depleted both granulocytic and monocytic MDSC subsets. Peptibody treatment was associated with inhibition of tumor growth in vivo, which was superior to that achieved with Gr-1-specific antibody. Immunoprecipitation of MDSC membrane proteins identified S100 family proteins as candidate targets. Our strategy may be useful to identify new diagnostic and therapeutic surface targets on rare cell subtypes, including human MDSCs. [ABSTRACT FROM AUTHOR]

Summary: Background: Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. Methods: We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722. Findings: We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15·4 months (IQR 10·1–21·0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). Interpretation: The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. Funding: National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center. [ABSTRACT FROM AUTHOR]

We conducted a prospective randomized phase II study to evaluate two chemotherapy regimens: (i) rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone ( R- HCVAD) alternating with rituximab, high-dose methotrexate, and cytarabine ( R- MA) and (ii) rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone ( R- CHOP) in diffuse large B-cell lymphoma ( DLBCL). This study randomized patients aged ≤60 years with DLBCL and an age-adjusted international prognostic index ≥2 to R- HCVAD/ R- MA or R- CHOP based on a Bayesian adaptive algorithm. Interim analysis of the first 26 eligible patients showed that the complete response rate ( CRR) was higher with R- HCVAD/ R- MA than R- CHOP ( P = 0·03); thus, R- CHOP arm was closed. In the final analysis, 49 and 10 eligible patients were treated in R- HCVAD/ R- MA and R- CHOP arms respectively; CRR were 82% and 60% respectively ( P = 0·13); 3-year progression-free survival ( PFS) rates were 75·7% and 77·8% respectively ( P = 0·53). In the R- HCVAD/ R- MA arm, 3-year PFS rates in patients aged 46-60 years and ≤45 years were 70·3% and 87·1% respectively ( P = 0·13), and the treatment-associated early mortality rate in patients >45 years was 12%. In conclusion, R- HCVAD/ R- MA is associated with excellent outcome in patients ≤45 years old. However, in patients >45 years old, R- HCVAD/ R- MA is associated with unacceptable mortality rates. [ABSTRACT FROM AUTHOR]

Current cancer vaccines induce tumor-specific T cell responses without sustained tumor regression because immunosuppressive elements within the tumor induce exhaustion of effector T cells and infiltration of immune-suppressive regulatory T cells (Tregs). Therefore, much effort has been made to generate agonistic Abs targeting members of the TNFR superfamily, such as OX40, 4-1BB, and GITR, expressed on effector T cells and Tregs, to reinvigorate T cell effector function and block Treg-suppressive function. In this article, we describe the development of a panel of anti-human OX40 agonistic mouse mAbs that could promote effector CD4+ and CD8+ T cell proliferation, inhibit the induction of CD4+ IL-10 -producing type 1 regulatory T cells, inhibit the expansion of ICOS+IL-10+ Tregs, inhibit TGF-β-induced FOXP3 expression on naive CD4+ T cells, and block natural Treg-suppressive function. We humanized two anti-human OX40 mAb clones, and they retained the potency of their parental clones. These Abs should provide broad opportunities for potential combination therapy to treat a wide realm of cancers and preventative vaccines against infectious diseases. [ABSTRACT FROM AUTHOR]

The article focuses on a study regarding the clinical trial of vorinostat in patients with peripheral T-cell lymphoma (PTCL) in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (VHOP). It informs that common toxicity in patients related to virinostat is diarrhoea and a patient started suffering from neutropenic fever despite giving granulocyte colony-stimulating factor (G-CSF). Other topics included angioimmunoblastic T-cell lymphoma and Histone deacetylase inhibitors.

Ag activation of the BCR may play a role in the pathogenesis of human follicular lymphoma (FL) and other B cell malignancies. However, the nature of the Ag(s) recognized by tumor BCRs has not been well studied. In this study, we used unbiased approaches to demonstrate that 42 (19.35%) of 217 tested FL Igs recognized vimentin as a shared autoantigen. The epitope was localized to the N-terminal region of vimentin for all vimentin-reactive tumor Igs. We confirmed specific binding to vimentin by using recombinant vimentin and by performing competitive inhibition studies. Furthermore, using indirect immunofluorescence staining, we showed that the vimentin-reactive tumor Igs colocalized with an anti-vimentin mAb in HEp-2 cells. The reactivity to N-terminal vimentin of IgG FL Igs was significantly higher than that of IgM FL Igs (30.4 versus 10%; p = 0.0022). However, vimentin-reactive FL Igs did not share CDR3 motifs and were not homologous. Vimentin was expressed in the T cell–rich regions of FL, suggesting that vimentin is available for binding with tumor BCRs within the tumor microenvironment. Vimentin was also frequently recognized by mantle cell lymphoma and multiple myeloma Igs. Our results demonstrate that vimentin is a shared autoantigen recognized by nonstereotyped FL BCRs and by the Igs of mantle cell lymphoma and multiple myeloma and suggest that vimentin may play a role in the pathogenesis of multiple B cell malignancies. These findings may lead to a better understanding of the biology and natural history of FL and other B cell malignancies. [ABSTRACT FROM AUTHOR]

p38 mitogen-activated protein kinase (MAPK), which is constitutively activated in human myeloma, has been implicated in bone destruction by this cancer, but the processes it recruits are obscure. In this study, we show that p38 activity in myeloma inhibits osteoblast differentiation and bone formation, but also enhances osteoclast maturation and bone resorption. p38 regulated the expression and secretion of the Wnt pathway antagonist DKK-1 and the monocyte chemoattractant MCP-1. Attenuating p38, DKK-1, or MCP-1 were each sufficient to reduce bone lesions in vivo. Although it is well known that DKK-1 inhibits osteoblast differentiation, we found that together with MCP-1, it could also promote osteoclast differentiation and bone resorption. The latter effects were mediated by enhancing expression of RANK in osteoclast progenitor cells and by upregulating secretion of its ligand RANKL from stromal cells and mature osteoblasts. In summary, our study defined the mechanisms by which p38 signaling in myeloma cells regulates osteoblastogenesis, osteoclastogenesis, and bone destruction. Our findings, which may have implications for bone invasion by other cancers where p38 is elevated, strongly suggests that targeting p38 for inhibition may offer an effective therapeutic approach to treat osteolytic bone lesions in patients with myeloma. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma frequently involved in the lymph nodes, bone marrow, spleen, and gastrointestinal tract. We examined the role of IL-6 in MCL. Human MCL cells expressed the membrane gp130 and soluble gp80, and some of them also secreted IL-6. Neutralizing autocrine IL-6 and/or blocking IL-6 receptors in IL-6+/gp80+ MCL cells inhibited cell growth, enhanced the rate of spontaneous apoptosis, and increased sensitivity to chemotherapy drugs. For IL-6or gp80low MCL cells, paracrine or exogenous IL-6 or gp80 protected the cells from stress-induced death. Knockdown of gp80 in gp80high MCL cells rendered the cells more sensitive to chemotherapy drugs, even in the presence of exogenous IL-6. In contrast, overexpression of gp80 in gp80low/IL-6+ MCL cells protected the cells from chemotherapy drug-induced apoptosis in vitro and compromised the therapeutic effect of chemotherapy in vivo. IL-6 activated the Jak2/ STAT3 and PI3K/Akt pathways in MCL, and the inhibition of these pathways completely or partially abrogated IL-6-mediated protection of MCL cells. Hence, our study identifies IL-6 as a key cytokine for MCL growth and survival and suggests that targeting the IL-6 pathway may be a novel way to improve the efficacy of chemotherapy in MCL patients. [ABSTRACT FROM AUTHOR]

The article presents information that the mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma. It informs that the MCL patients show a reduced response to the conventional therapy and therapeutic interventions including monoclonal antibody-based therapy and stem cell transplantation. It mentions that despite the approval by the U.S. Food and Drug Administration for the treatment of patients with relapsed MCL, bortezomib has shown reduced effects.

Immunotherapy with therapeutic idiotype vaccines offers promise for treatment of B-cell malignancies. However, identifica-tion of novel immunogenic lymphoma-associated antigens that are universally expressed is necessary to overcome the barriers of patient-specific idiotype vac-cines. Here, we determined whether T-cell leukemia/lymphoma 1 (TCL1) oncopro-tein encoded by the TCL1 gene could be a target for immunotherapy of B-cell malig-nancies. We show that TCL1 mRNA and protein are selectively expressed in normal B cells but markedly hyperexpressed in multiple human B-cell lymphomas, in-cluding follicular lymphoma, chronic lym-phocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and splenic marginal zone B-cell lymphoma. We dem-onstrated that TCL1-specific CD8+ T cells can be generated from HLA-A*0201 (HLA-A2)+ normal donors and identified TCLI71-78 (LLPIMWQL) as the minimal epitope recognized by these T cells. More importantly, TCL171-78 peptide-specific T cells were present In the peripheral blood and tumor-infiltrating lymphocytes of lymphoma patients, could be expanded in vitro, and lysed autologous tumor cells but not normal B cells in an HLA-A2-restricted manner. Our results suggest thatTCLI is naturally processed and pre-sented on the surface of lymphoma cells for recognition by cytotoxic T cells and can serve as a novel target for develop-ment of immunotherapeutic strategies against common B-cell lymphomas. [ABSTRACT FROM AUTHOR]

In the present study, we evaluated the efficacy and safety of rituximab In combi-nation with standard doxorubicin, bleomy-cin, vinblastine, and dacarbazine (RABVD) in patients with classical Hodgkin lym-phoma (cHL). In this phase 2 study, patients with chemotherapy-naive, advanced-stage cHL were treated with rituximab 375 mg/m2 weekly for 6 weeks and standard ABVD for 6 cycles. The primary outcome was event-free survival (EFS) at 5 years. Eighty-five patients were enrolled, of whom 78 were eligible. With a median follow-up duration of 68 months (range, 26-110), and based on an intent-to-treat analysis, the 5-year EFS and overall survival rates were 83% and 96%, respec-tively. The 5-year EFS for patients with stage lll/IV cHLwas 82%. Furthermore, the 5-year EFS for patients with an Interna-tional Prognostic Score of 0-2 was 88% and for those with a score of > 2, it was 73%. The most frequent treatment-related grade 3 or 4 adverse events were neutro-penia (23%), fatigue (9%), and nausea (8%). Our results demonstrate that the addition of rituximab to ABVD is safe and has a promising clinical activity in pa-tients with advanced-stage cHL. These data are currently being confirmed in a multi-center randomized trial. This trial has been completed and is registered with www.clini-caltrials.gov as NCT00504504. {Blood. 2012; 119(18):4123-4128) [ABSTRACT FROM AUTHOR]

Although bortezomib is clinically approved for the treatment of mantle cell lymphoma (MCL), only limited effects of this treatment have been demonstrated. To improve survival for bortezomib-resistant patients, it is necessary to develop new therapeutic strategies. In the present study, we used biochemical and molecular methodologies to demonstrate that tissue transglutaminase (TG) activates downstream NF-κB signaling pathways. The signaling axis from TG to NF-κB could be a new therapeutic target to overcome bortezomib resistance in MCL. TG2 is a calcium-dependent protein cross-linking enzyme reported to be overexpressed in various cancer cells. We found that MCL cells expressed elevated levels of TG2 and that the modification of TG2 activities altered NF-κB expression and downstream signaling in MCL cells. When TG2 signaling was inhibited by calcium blockers, the combination of a calcium blocker (perillyl alcohol) with bortezomib suppressed NF-κB expression and improved the cytotoxicity of bortezomib in MCL cells. Our study is the first to show the expression of TG2 and the contribution of TG2 to NF-κB signaling in MCL. TG2 inhibition may be used as an alternative target anti-MCL therapy, and calcium blockers may be combined with bortezomib to overcome the bortezomib resistance in MCL. [ABSTRACT FROM AUTHOR]

Dickkopf-1 (DKK1), broadly expressed in myeloma cells but highly restricted in normal tissues, together with its functional roles as an osteoblast formation inhibitor, may be an ideal target for immunotherapy in myeloma. Our previous studies have shown that DKK1 (peptide)-specific CTLs can effectively lyse primary myeloma cells in vitro. The goal of this study was to examine whether DKK1 can be used as a tumor vaccine to elicit DKK1-specific immunity that can control myeloma growth or even eradicate established myeloma in vivo. We used DKK1-DNA vaccine in the murine MOPC-21 myeloma model, and the results clearly showed that active vaccination using the DKK1 vaccine not only was able to protect mice from developing myeloma, but it was also therapeutic against established myeloma. Furthermore, the addition of CpG as an adjuvant, or injection of B7H1-blocking or OX40-agonist Abs, further enhanced the therapeutic effects of the vaccine. Mechanistic studies revealed that DKK1 vaccine elicited a strong DKK1- and tumor-specific CD4+ and CD8+ immune responses, and treatment with B7H1 or OX40 Abs significantly reduced the numbers of IL-10-expressing and Foxp3+ regulatory T cells in vaccinated mice. Thus, our studies provide strong rationale for targeting DKK1 for immunotherapy of myeloma patients. [ABSTRACT FROM AUTHOR]

Abstract: Patients with malignant non-Hodgkin''s lymphomas (NHL) of B-cell lineages relapse despite initial anti-tumor response to chemotherapy or antibody treatments. Failure to eliminate the tumor is often because of inadequate priming, low cell numbers and suboptimal phenotype of effector T cells. Here we describe a new biomaterial-based controlled-release paradigm to treat weakly immunogenic NHLs by in-situ amplifying the number of functional, antigen-specific T-helper 1 (Th1) cells following immunotherapy. An injectable, synthetic immune priming center (sIPC) consisting of an in-situ crosslinking, chemokine-carrying hydrogel and both DNA- and siRNA dual-loaded microparticles, is reported. This sIPC chemo attracts a large number of immature dendritic cells (DCs) at the site of administration and efficiently co-delivers both DNA antigens and interleukin-10 (IL10)-silencing siRNA to those cells. Using a murine model of A20 B cell lymphoma, we demonstrate that combination of DNA-antigen delivery and IL10 silencing, synergistically activate recruited immature DCs and cause a strong shift towards Th1 response while suppressing Th2 and Th17 cytokines. sIPC-based immunotherapy showed 45% more CD8+ cytotoxic T cell (CTL) response and 53% stronger CD4+ CTL activity compared to naked DNA vaccine. In addition, in-vivo sIPC immunization induced significant protection (p <0.01) against subsequent tumor challenge. Such a multi-modal, injectable system that simultaneously delivers chemokines, siRNA and DNA antigens to DCs marks a new approach to in-situ priming and modulation during immunotherapy and could provide effective vaccination strategies against cancers and infectious diseases. [Copyright &y& Elsevier]

Monoclonal antibodies (mAbs) specific for human β-microglobulin (βM) have been shown to induce tumour cell apoptosis in haematological and solid tumours via recruiting major histocompatibility complex (MHC) class I molecules into and excluding cytokine receptors from the lipid rafts. Based on these findings, we hypothesized that IgM anti-βM mAbs might have stronger apoptotic effects because of their pentameric structure. Our results showed that, compared with IgG mAbs, IgM anti-βM mAbs exhibited stronger tumouricidal activity in vitro against different tumour cells, including myeloma, mantle cell lymphoma, and prostate cancer, and in vivo in a human-like xenografted myeloma mouse model without damaging normal tissues. IgM mAb-induced apoptosis is dependent on the pentameric structure of the mAbs. Disrupting pentameric IgM into monomeric IgM significantly reduced their ability to induce cell apoptosis. Monomeric IgM mAbs were less efficient at recruiting MHC class I molecules into and exclusion of cytokine receptors from lipid rafts, and at activating the intrinsic apoptosis cascade. Thus, we developed and validated the efficacy of anti-βM IgM mAbs that may be utilized in the clinical setting and showed that IgM anti-βM mAbs may be more potent than IgG mAbs at inducing tumour apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: We recently reported that administration of low doses of myotoxins at vaccination sites potentiated antigen-specific T-cell immunity induced by genetic cancer vaccines in mice, an effect which was superior to TLR agonists. In the current study, we found unexpectedly that the mechanism of this potent adjuvant effect was immune-mediated. Myotoxins induced sterile inflammation at vaccination sites, associated with a predominant infiltration of dendritic cells (DC). Inhibition of DC recruitment abrogated the immune stimulation effect of myotoxins, suggesting the requirement for DC. Genetic profiling of myotoxin-treated tissues revealed characteristics of an immune microenvironment with up-regulation of chemokines, proinflammatory cytokines, Toll-like receptors (TLR) and their endogenous ligands, and activation of innate immunity. Mechanistic experiments in vivo also elucidated the requirement for genes triggering DC maturation including TLR signaling and CD40. These studies suggest that myotoxins-induced sterile inflammation generates a favorable microenvironment that promotes multiple stages in the development of adaptive immunity. This novel mechanism of immune potentiation may be exploited for development of adjuvants for genetic vaccines against infectious pathogens and cancer. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) outcomes have improved over the last two decades; however, late relapses occur. Bortezomib has shown single agent activity of 33% in relapsed MCL and has an additive/synergistic effect in vitro when combined with drugs currently used to treat MCL. We hypothesized that a combination of bortezomib with current intense non-transplant chemoimmunotherapy might prevent late relapses. The toxicity of bortezomib when combined with methotrexate and cytarabine is unknown. Patients aged 18–79 years with untreated aggressive MCL were treated with R-HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with rituximab-methotrexate/cytarabine (R-M/A). Bortezomib was added to the R-Hyper-CVAD combination as a fixed dose of 1·3 mg/m2 IV on days 2 and 5 and was added to the R-M/A regimen after rituximab, in increasing doses of 0·7, 1, and 1·3 mg/m2 in cohorts of three patients. Twenty patients were assessed for toxicity of the regimen. The principal toxicity was haematological and did not differ from that observed with a similar regimen without the bortezomib. In particular, there was no pulmonary or neurological dose-limiting toxicity, showing that bortezomib can be safely combined with R-HyperCVAD and R-M/A. [ABSTRACT FROM AUTHOR]

HIV vaccine candidates with improved immunogenicity and induction of mucosal T-cell immunity are needed. A prime-boost strategy using a novel HIV glycoprotein 120 DNA vaccine was employed to immunize rhesus macaques. The DNA vaccine encoded a chimeric gp120 protein in fusion with monocyte chemo attractant protein-3, which was hypothesized to improve the ability of antigen-presenting cells to capture viral antigen through chemokine receptor-mediated endocytosis. DNA vaccination induced virus-reactive T cells in peripheral blood, detectable by T cell proliferation, INF? ELISPOT and sustained IL-6 production, without humoral responses. With a peptide-cocktail vaccine containing a set of conserved polypeptides of HIV-1 envelope protein, given by nasogastric administration, primed T-cell immunity was significantly boosted. Surprisingly, long-term and peptide-specific mucosal memory T-cell immunity was detected in both vaccinated macaques after one year. Therefore, data from this investigation offer proof-of-principle for potential effectiveness of the prime-boost strategy with a chemokine-fused gp120 DNA and warrant further testing in the nonhuman primate models for developing as a potential HIV vaccine candidate in humans. [ABSTRACT FROM AUTHOR]

Controlled modulation of T-cell response during immunotherapy, especially the balance between T helper 1 (Th1) and Th2 responses, is critical for generating effective immune response. Here we report that dual delivery of interleukin 10 (IL-10)-targeted small interfering RNA (siRNA) and DNA vaccines to dendritic cells (DCs), using a single particle carrier, efficiently enhances immune response and modulates it toward a stronger Th1 phenotype. Surface-functionalized polymer microparticles (MPs) carrying both IL-10-targeted siRNA and DNA antigens exhibited effective gene silencing, DNA transfection, and synergistically enhanced upregulation of maturation markers in primary DCs leading to increased T-cell proliferation, in vitro. Mice immunized with these dual-delivery carriers demonstrated a significant “switch” toward Th1 response as evidenced by increase in interferon γ (IFN-γ) production and decrease in IL-4 production by CD4+ T cells. This further led to enhanced antiviral cytotoxic T-lymphocyte activity. Such dual siRNA–DNA delivery provides a novel strategy to precisely control the type and strength of T-cell response during immunotherapy.Molecular Therapy (2008) 16 12, 2011–2021 doi:10.1038/mt.2008.206 [ABSTRACT FROM AUTHOR]

The article presents the clinical trial of several antineoplastic agents including rituximab, methotrexate, and cytarabine which treat patients with refractory mantle cell lymphoma (MCL) in the U.S. It notes that toxicity, neutropenic fever, and thrombocytopenia are the side effects of the anticancer agents. Moreover, it emphasizes the effectiveness of chemotherapeutic agents including cyclophosphamide, vincristine, and doxorubicin on treating MCL.

Abstract: Adoptive therapy with antigen-specific T cells is a promising approach for the treatment of infectious diseases and cancer. However, cloning of antigen-specific T cells by the traditional approach of limiting dilution is a time-consuming, laborious, and inefficient process. Here, we describe a novel flow cytometric strategy for rapid isolation of human tumor antigen-specific T-cell clones by using T-cell receptor (TCR) Vβ antibodies in combination with carboxyfluorescein succinimidyl ester (CFSE)-based proliferation assay. The CFSE dilution following antigen stimulation identified proliferating antigen-specific T cells, and the TCRVβ antibodies allowed distinguishing T cells at the clonal level from a heterogeneous T-cell population. This method of TCRVβ/CFSE dilution was used for the isolation of four different human lymphoma and melanoma-specific CD4+ and CD8+ T-cell clones reactive against defined and undefined tumor antigens. Isolated tumor-specific T-cell clones could be expanded to large numbers ex vivo while maintaining phenotype, function, and tumor antigen specificity. The method was simple, efficient, and reproducible, and may have potential application for the development of adoptive immunotherapeutic strategies. [Copyright &y& Elsevier]

Abstract: We investigated the antitumor effect of survivin DNA vaccine in murine pancreatic and lymphoma models, and if xenogenic survivin can generate stronger immune response. We found that mice vaccinated with either human or mouse survivin DNA have significantly slower tumor growth and longer survival than those vaccinated with vector DNA. There was no significant difference between groups that received human and mouse survivin DNA. Lymphocyte infiltration was greater in tumors of mice immunized with survivin DNA than in tumors of control mice. We conclude that survivin DNA vaccine generated specific antitumor effects with increased lymphocyte infiltration at the tumor sites. [Copyright &y& Elsevier]