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Journal of Immunotherapy

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https://www.readbyqxmd.com/read/27875387/clinical-response-rates-from-interleukin-2-therapy-for-metastatic-melanoma-over-30-years-experience-a-meta-analysis-of-3312-patients
#1
Richard Bright, Brendon J Coventry, Nathan Eardley-Harris, Nancy Briggs
Interleukin-2 (IL-2), initially used in 1986, can induce clinical regression-complete responses (CR) and partial responses (PR) of metastatic malignant melanoma. IL-2 has been used alone or in combination, and in different dosage schedules, as an immunotherapeutic agent for melanoma treatment. This meta-analysis aimed to document and evaluate the spectrum of reported clinical response rates from the combined experience of almost 30 years of IL-2 clinical usage. Clinical trials using IL-2 for metastatic melanoma therapy that reported: dosage, combinations, study details, definitions and clinical CR, PR, and overall response (OR) rates were included...
January 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27846054/sequencing-treatment-in-brafv600-mutant-melanoma-anti-pd-1-before-and-after-braf-inhibition
#2
Douglas B Johnson, Eirini Pectasides, Emily Feld, Fei Ye, Shilin Zhao, Romany Johnpulle, Ryan Merritt, David F McDermott, Igor Puzanov, Donald Lawrence, Jeffrey A Sosman, Elizabeth Buchbinder, Ryan J Sullivan
Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n=56) versus those that received BRAF±MEK inhibitors (BRAFi) first (n=58)...
January 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27828929/the-characteristics-of-naive-like-t-cells-in-tumor-infiltrating-lymphocytes-from-human-lung-cancer
#3
Si Yuan Sheng, Yong Gu, Chuan Gang Lu, Ying Ying Tang, Jian Yong Zou, Yu Qing Zhang, Rong Fu Wang, Hai Hong
Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TILs) or genetically modified lymphocytes from TILs is a new effective approach, but the application of TIL immunotherapy is still limited in many solid tumors. Knowledge of the classification and function of TILs is important to develop personalized immunotherapy with TILs in non-small lung cancer (NSCLC). In this study, we show the characteristics of T-cell subsets in TILs isolated from NSCLC. CD3 CD8 CD45RA T cells outnumbered CD3 CD4 CD45RA T cells in CD45RA TILs, but it was the opposite in CD45RO TILs...
January 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27684455/durable-response-of-metastatic-squamous-cell-carcinoma-of-the-skin-to-ipilimumab-immunotherapy
#4
Fiona Day, Mahesh Kumar, Linda Fenton, Craig Gedye
A 72-year-old male patient was receiving second-line chemotherapy for metastatic squamous cell carcinoma of the skin (SCCS) when he was diagnosed with concurrent metastatic melanoma (BRAF mutant). Chemotherapy was ceased and he was treated with 4 cycles of ipilimumab immunotherapy. The patient experienced clinical benefit and durable remission in both malignancies and remains free of cancer progression 8 months after the last cycle of ipilimumab. Response of SCCS to ipilimumab has not been previously described, however this case and recent reports of pembrolizumab efficacy confirm the critical role of the immune system in SCCS pathogenesis and suggest further exploration of checkpoint immunotherapy for the treatment of this disease...
January 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27681378/synthetic-poly-l-glutamic-acid-conjugated-cpg-exhibits-antitumor-efficacy-with-increased-retention-in-tumor-and-draining-lymph-nodes-after-intratumoral-injection-in-a-mouse-model-of-melanoma
#5
Qing Ma, Dapeng Zhou, Elizabeth S DeLyria, Xiaoxia Wen, Wei Lu, Prakash Thapa, Chengwen Liu, Dan Li, Roland L Bassett, Willem W Overwijk, Patrick Hwu, Chun Li
There is an urgent need for new clinically applicable drug-delivery methods to enhance accumulation of immune-activating drugs in tumors. We synthesized a poly(L-glutamic acid)-CpG ODN2216 conjugate (PG-CpG) and injected it intratumorally into C57BL/6 mice bearing subcutaneous B16-ovalbumin melanoma. PG-CpG elicited the same potent antitumoral activity as CpG with respect to reducing tumor growth and triggering antigen-specific CD8 T-cell responses in this well-established solid tumor model. Moreover, PG-CpG was retained significantly longer in both tumor and draining lymph nodes than was free CpG after intratumoral injection...
January 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27741091/analysis-of-the-abscopal-effect-with-anti-pd1-therapy-in-patients-with-metastatic-solid-tumors
#6
Jéssica Ribeiro Gomes, Rafael A Schmerling, Carolina K Haddad, Douglas J Racy, Robson Ferrigno, Erlon Gil, Pedro Zanuncio, Antônio C Buzaid
Abscopal effect is a rare phenomenon characterized by tumor regression of untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied the probability of abscopal effect with radiotherapy associated with anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This study is a retrospective analysis of patients treated with nivolumab or pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer at Antônio Ermírio de Moraes Oncology Center, Brazil. To be eligible for this analysis, patients must have had unequivocal evidence of disease progression on anti-PD1 therapy and subsequent radiotherapy for any tumor site while still receiving anti-PD1...
November 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27741090/exogenous-il-2-induces-foxp3-th17-cells-in-vivo-in-melanoma-patients
#7
Maggie L Diller, Ragini R Kudchadkar, Keith A Delman, David H Lawson, Mandy L Ford
Th17 cells represent a distinct subset of CD4 effector T cells with potent pathogenic qualities, capable of directly mediating tumor cell destruction. IL-2 has frequently been shown to have a negative effect on Th17 differentiation while supporting regulatory T-cell (FoxP3CD4, TREG) growth and development in both in vitro models and in vivo animal models. We investigated the effect of in vivo IL-2 on both the Th17 and FoxP3CD4 T-cell compartments in a human model of cancer. High-dose IL-2 (HDIL-2) was administered at a dose of 720,000 IU/kg to patients with melanoma (n=7) and peripheral blood was collected at baseline and at 24, 48, 72, and 96 hours posttreatment...
November 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27741089/t-cell-therapy-enabling-adenoviruses-coding-for-il2-and-tnf%C3%AE-induce-systemic-immunomodulation-in-mice-with-spontaneous-melanoma
#8
Siri Tähtinen, Carolin Blattner, Markus Vähä-Koskela, Dipongkor Saha, Mikko Siurala, Suvi Parviainen, Jochen Utikal, Anna Kanerva, Viktor Umansky, Akseli Hemminki
The immunosuppressive microenvironment of solid tumors renders adoptively transferred T cells hypofunctional. However, adenoviral delivery of immunostimulatory cytokines IL2 and TNFα can significantly improve the efficacy of adoptive T-cell therapy. Using ret transgenic mice that spontaneously develop skin malignant melanoma, we analyzed the mechanism of action of adenoviruses coding for IL2 and TNFα in combination with adoptive transfer of TCR-transgenic TRP-2-specific T cells. Following T-cell therapy and intratumoral virus injection, a significant increase in antigen-experienced, tumor-reactive PD-1 CD8 T cells was seen in both cutaneous lesions and in metastatic lymph nodes...
November 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27662340/pembrolizumab-triggered-uveitis-an-additional-surrogate-marker-for-responders-in-melanoma-immunotherapy
#9
Stefan Diem, Fabienne Keller, Reinhard Rüesch, Samia A Maillard, Daniel E Speiser, Reinhard Dummer, Marco Siano, Ursula Urner-Bloch, Simone M Goldinger, Lukas Flatz
Immunotherapy leads to significantly prolonged survival of patients with metastatic melanoma. Autoimmune side effects including colitis, dermatitis, and endocrine abnormalities are common in patients treated with ipilimumab [anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4)]. Antibodies such as pembrolizumab that interfere with the PD-1 (programmed cell death 1)/PD-L1 pathway show greater efficacy and less toxicity than ipilimumab. Here we report 2 cases of pembrolizumab-induced uveitis associated with complete or partial tumor response...
November 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27662339/radiotherapy-to-control-limited-melanoma-progression-following-ipilimumab
#10
Lauren M Kropp, Jennifer F De Los Santos, Svetlana B McKee, Robert M Conry
Durable local control of irradiated cancer and distant abscopal effects are presumably immune mediated. To evaluate the role of radiotherapy (RT) for limited progression after anti-CTLA4 checkpoint inhibition, medical records of all patients with surgically incurable stage III or IV melanoma from a single institution who received ipilimumab as first-line immunotherapy and subsequent RT were reviewed. Sixteen patients who received RT to all sites of limited melanoma progression were analyzed. Eight patients with an incomplete initial response to ipilimumab received RT to new or progressive disease, whereas the remaining 8 patients with a complete initial response to ipilimumab received RT to sites of subsequent recurrence...
November 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27631893/heterogeneity-of-specific-cd4-and-cd8-t-cells-stimulated-by-cmv-pp65-and-ie1-antigens
#11
Elena Albiero, Eliana Amati, Elke Baumeister, Hermann Einsele, Götz U Grigoleit, Francesco Rodeghiero
Characterization of human cytomegalovirus-specific T cells (CMV-T) is of critical importance for their potential use in adoptive immunotherapy after allogeneic hematopoietic stem cell transplantation. Background frequencies of CMV-T in peripheral blood mononuclear cells (PBMCs) of CMV-seropositive healthy subjects are usually very low, hence the requirement for prolonged culture time and multiple stimulations to expand them. The evaluation of the end-culture specificity and composition has sometimes been neglected or difficult to assess in these settings...
November 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27564312/immune-monitoring-of-patients-treated-with-a-whole-cell-melanoma-vaccine-engineered-to-express-4-1bbl
#12
Roni Engelstein, Sharon Merims, Galit Eisenberg, Jonathan Cohen, Stephen Frank, Tamar Hamburger, Shoshana Frankenburg, Ilan Ron, Ruth Isacson, Tal Grenader, Hanna Steinberg, Cyrille J Cohen, Tamar Peretz, Michal Lotem
CD8 lymphocytes are mandatory mediators of tumor regression. To enhance their specific antitumor activity, we aimed to improve a melanoma cell-based vaccine by transfecting it with 4-1BB ligand, a costimulatory and immune modulatory molecule. Thirty-four American Joint Committee on Cancer (AJCC) stage IIB-IV patients were vaccinated with a melanoma antigen-rich cell line engineered to express HLA-A2 and 4-1BBL (M20/A2/BBL). Twelve serially recruited patients were monitored for interferon γ expression and CD107a mobilization before and after vaccination...
October 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27548034/vaccination-against-human-papilloma-viruses-leads-to-a-favorable-cytokine-profile-of-specific-t-cells
#13
Stefanie Luckau, Tim P Wehrs, Sven Brandau, Peter A Horn, Monika Lindemann
Several human papilloma viruses (HPV) are known to cause malignant transformation. The high-risk type HPV 16 is associated with cervical carcinoma and head and neck squamous cell carcinoma. HPV 16-positive tumor cells exclusively carry the HPV 16 oncogenes E6 and E7. These oncogenes appear as excellent targets for an adoptive immunotherapy. We here addressed the question whether specific T cells from HPV-vaccinated healthy volunteers could be especially suitable for an HPV-specific cellular immunotherapy. Of note, vaccines contain HPV 16...
October 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27548033/programmed-death-ligand-1-on-antigen-presenting-cells-facilitates-the-induction-of-antigen-specific-cytotoxic-t-lymphocytes-application-to-adoptive-t-cell-immunotherapy
#14
Tatsunori Goto, Tetsuya Nishida, Erina Takagi, Kotaro Miyao, Daisuke Koyama, Reona Sakemura, Ryo Hanajiri, Keisuke Watanabe, Nobuhiko Imahashi, Seitaro Terakura, Makoto Murata, Hitoshi Kiyoi
Programmed death-ligand 1 (PD-L1) binds to programmed death-1 (PD-1) on activated T cells and contributes to T-cell exhaustion. PD-L1 expressed on antigen-presenting cells (APCs) could be thought to inhibit the induction of Ag-specific cytotoxic T lymphocytes (CTLs) by transducing negative signal into T cells; however, the roles of PD-L1 on APCs have not yet been well examined. Therefore, we evaluated the roles of PD-L1 on APCs in the induction of Ag-specific CTLs. CD3 T cells isolated from cytomegalovirus (CMV)-seropositive healthy donors were stimulated with mature dendritic cells pulsed with CMV pp65-derived HLA-restricted peptides in the presence of anti-PD-L1 blocking antibody...
October 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27488724/an-in-vitro-model-that-predicts-the-therapeutic-efficacy-of-immunomodulatory-antibodies
#15
Min Dai, Yuen Yee Yip, Ingegerd Hellstrom, Karl Erik Hellstrom
Immunomodulatory monoclonal antibodies (mAbs) have efficacy in patients with advanced cancer and are the focus of intensive research. However, cures are infrequent and responses vary among tumor types and among subjects with the same tumor. An in vitro test would be valuable to determine the most effective mAb combination for a given case and to evaluate novel agents. Toward this goal, we investigated the ability of various mAb combinations to generate a tumor-destructive immune response in vitro in the presence of lymphoid cells from mice with established TC1 lung carcinoma, B16 melanoma, or SW1 melanoma...
October 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27428265/innovation-in-bladder-cancer-immunotherapy
#16
H Barton Grossman, Donald L Lamm, Ashish M Kamat, Stephen Keefe, John A Taylor, Molly A Ingersoll
Bladder cancer is understudied despite its high prevalence and its remarkable response to immunotherapy. Indeed, funding for studies to explore mechanisms of tumor immunity and novel new therapeutics is disproportionately lower for bladder cancer in comparison with malignancies of the breast, prostate, or lung. However, the recent successes of checkpoint blockade therapy suggest that new therapeutic strategies are on the horizon for bladder cancer. Here, we give a perspective into the evolution of bladder cancer therapy, focusing on strategies to treat high-risk nonmuscle invasive disease, followed by a discussion of recent advances in the treatment of muscle invasive bladder cancer and their potential applicability to lower stage disease...
October 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27488725/engineering-hematopoietic-cells-for-cancer-immunotherapy-strategies-to-address-safety-and-toxicity-concerns
#17
Diana Resetca, Anton Neschadim, Jeffrey A Medin
Advances in cancer immunotherapies utilizing engineered hematopoietic cells have recently generated significant clinical successes. Of great promise are immunotherapies based on chimeric antigen receptor-engineered T (CAR-T) cells that are targeted toward malignant cells expressing defined tumor-associated antigens. CAR-T cells harness the effector function of the adaptive arm of the immune system and redirect it against cancer cells, overcoming the major challenges of immunotherapy, such as breaking tolerance to self-antigens and beating cancer immune system-evasion mechanisms...
September 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27428264/constructing-tumor-vaccines-targeting-for-vascular-endothelial-growth-factor-vegf-by-dna-shuffling
#18
Nana Bie, Xiuyun Zhao, Zhitao Li, Gaofu Qi
Most of tumor antigens are self-proteins with poor antigenicity because of immune tolerance. Here, we describe DNA shuffling for overcoming the tolerance of tumor antigens such as vascular endothelial growth factor (VEGF), a growth factor associated with tumor angiogenesis. VEGF genes from mouse, rat, human, and chicken were randomly assembled to chimeric genes by DNA shuffling for constructing an expression library, then screened by PCR, SDS-PAGE, and immunization. A chimeric protein named as No. 46 was selected from the library with the strongest immunotherapy effects on mouse H22 hepatocellular carcinoma, which could induce long-lasted and high level of antibodies recognizing VEGF in mice...
September 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27404943/improved-anti-treg-vaccination-targeting-foxp3-efficiently-decreases-regulatory-t-cells-in-mice
#19
Neda Mousavi Niri, Arash Memarnejadian, Younes Pilehvar-Soltanahmadi, Mohammadreza Agha Sadeghi, Mehdi Mahdavi, Nasim Kheshtchin, Samaneh Arab, Afshin Namdar, Farhad Jadidi, Nosratollah Zarghami, Jamshid Hajati
INTRODUCTION: The critical role of regulatory T (Treg) cells in dampening immune responses against tumor cells is apparent. Therefore, several methods have been introduced for eliminating Treg. Among them, inducing immune responses against Treg cells expressing Foxp3 transcription factor is a hopeful approach to decrease the frequency of Tregs. In current study, we used the chimeric FoxP3-Fc(IgG) fusion construct/protein to effectively stimulate the immune responses against Treg cells...
September 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27404942/an-association-between-glatiramer-acetate-and-malignant-melanoma
#20
John Walker, AnneLiese Smylie, Michael Smylie
A 43-year-old female receiving immunomodulatory therapy with glatiramer acetate (copaxone, GA) for relapsing, remitting multiple sclerosis was diagnosed with stage IIIB melanoma that recurred <7 months after resection and lymphadenectomy. In preparation for systemic therapy the patient discontinued GA, and shortly thereafter experienced spontaneous and complete clinical and radiographic resolution of her disease. The development and subsequent regression of melanoma in this patient may be due to the use and subsequent discontinuation of GA, and our discussion of the case includes the potential immunologic mechanisms that may provide an explanation for our findings...
September 2016: Journal of Immunotherapy
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