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https://www.readbyqxmd.com/read/29052220/efficacy-from-strange-sources
#1
Lawrence Lesko
Reverse translation (RT) refers to perceptions and observations of clinical outcomes, both beneficial and harmful, that can lead to a hypothesis intended to identify a new use of a drug that is different than the original use. I provide a panoramic view of successes in RT from the historic discovery of penicillin to the contemporary development of CAR T therapies. I delineate the core principles of RT that shift discovery from serendipity to a systematic strategy based on target identification based on causal biology, pharmacodynamic biomarkers that recapitulates disease pathophysiology, confirmation of target engagement by clinical proof of concept studies, and optimal selection of dose and interval...
October 20, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29052093/emerging-small-molecule-approaches-to-enhance-the-antimyeloma-benefit-of-proteasome-inhibitors
#2
James J Driscoll, Magen Brailey
Multiple myeloma (MM) is a clonal plasma cell malignancy which, despite recent treatment advances, remains incurable in the vast majority of the over 118,000 patients in the USA afflicted with this disease. Treatment of MM has dramatically improved in the past decade with the introduction of new drugs into therapeutic strategies in both the frontline and relapse settings that has led to a significant improvement in the median overall survival (OS). These drugs have been incorporated into clinical guidelines and transformed the treatment approach to MM...
October 19, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29050700/the-what-when-and-how-of-car-t-cell-therapy-for-all
#3
REVIEW
Noelle Frey
Chimeric Antigen Receptor (CAR) T cells that have been engineered to target CD19 have shown great promise in patients with relapsed and refractory B cell acute lymphocytic leukemia with remission rates of 70-90%. Some remissions have successfully bridged patients to a curable allogeneic stem cell transplant, some responses have been durable without further treatment, and some patients have achieved durable remissions for relapsed ALL after allogeneic stem cell transplant. Cytokine release syndrome, correlating with the in vivo activation and expansion of T cells, and neurologic toxicity are the most significant side effects and approaches to better understand and manage these events are the subject of ongoing clinical trials...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050693/how-should-we-treat-older-adults-with-ph-adult-all-and-what-novel-approaches-are-being-investigated
#4
REVIEW
Matthew J Wieduwilt
Treatment of older patients with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia presents unique challenges. Advanced age, comorbidities, high treatment-related death rates with traditional chemotherapy, and relapse combine to yield poor survival. Reduced-intensity induction with BCR-ABL1 targeted tyrosine kinase inhibitors (TKIs) and corticosteroids yields CR rates 96-100% with no induction mortality but relapse is nearly certain without effective consolidation. Few clinical trials provide guidance on optimal consolidation for older Ph+ ALL...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050075/-specific-cytotoxicity-of-a-novel-her2-based-chimeric-antigen-receptor-modified-t-lymphocytes-against-her2-positive-tumor-cells
#5
H J Tang, Y Q Liu, X C Bian, H L Feng, B Gu, H Sun, C X Zuo, F Y Zhou, J Liu
Objective: To construct the third generation chimeric antigen receptor based on a novel humanized anti-HER2 H1-2 scFv, and to investigate the specific cytotoxicity of H1-2 CAR modified T lymphocytes(CAR-T) against HER2(+) tumor cells. Method: The expression cassette of the third generation CAR gene and anti-HER2 H1-2 scFv were constructed and cloned into lentivirus transfer plasmid, and then the third generation H1-2 CAR was transduced into human T lymphocytes using lentivirus.Enzyme linked immunosorbent assay was used to detect the expression of cytokines IL2, and LDH release assay was used to detect the cytotoxic effect of the H1-2 CAR-T...
October 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/29048935/chimeric-antigen-receptor-t-cell-therapy-for-solid-tumors-require-new-clinical-regimens
#6
Jinjing Xu, Kang Tian, Haixu Zhang, Liantao Li, Hongyan Liu, Jingjie Liu, Qing Zhang, Junnian Zheng
Chimeric antigen receptor modified T cell (CAR-T) therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. Nevertheless, this success has not yet been extrapolated to solid tumors. This review focuses on new clinical regimens that could improve the therapeutic efficacy of CAR-T in solid tumors. Areas covered: Herein, the authors reviewed recent clinical trials using CAR-T therapies for the treatment of solid tumors. Specifically, this review covered the following areas: (1) the current status of CAR-T cells in the treatment of solid tumors; (2) the major factors constraining the efficacy of CAR-T cells in solid tumors; and (3) opinions regarding the future of CAR-T as a treatment for solid tumors...
October 19, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29046826/incorporation-of-functional-elements-enhances-the-antitumor-capacity-of-car-t-cells
#7
REVIEW
Le Qin, Ruocong Zhao, Peng Li
As chimeric antigen receptor (CAR) T cells have displayed an unprecedented efficacy in the treatment of CD19-positive malignances, it is believed that this cell therapy will be a milestone in the history of mankind's conquering of cancer. However, there are some issues that restrict CAR T cells from reaching their optimal anti-tumor capacity, especially in the treatment of solid tumors. Inhibitory cytokines, immune checkpoint molecules, hypoxia and other adverse factors have been reported to be involved in this process...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29043880/concurrent-therapy-of-chronic-lymphocytic-leukemia-and-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-utilizing-cd19-targeted-car-t-cells
#8
Mark B Geyer, Shwetha H Manjunath, Andrew G Evans, Jae H Park, Marco L Davila, Corey S Cutler, Xiuyan Wang, Yongzeng Wang, Brigitte Senechal, Isabelle Rivière, Michel Sadelain, Jane L Liesveld, Renier J Brentjens
No abstract text is available yet for this article.
October 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29039115/genome-editing-technologies-in-adoptive-t-cell-immunotherapy-for-cancer
#9
REVIEW
Nathan Singh, Junwei Shi, Carl H June, Marco Ruella
PURPOSE OF REVIEW: In this review, we discuss the most recent developments in gene-editing technology and discuss their application to adoptive T cell immunotherapy. RECENT FINDINGS: Engineered T cell therapies targeting cancer antigens have demonstrated significant efficacy in specific patient populations. Most impressively, CD19-directed chimeric antigen receptor T cells (CART19) have led to impressive responses in patients with B-cell leukemia and lymphoma. CTL019, or KYMRIAH™ (tisagenlecleucel), a CD19 CAR T cell product developed by Novartis and the University of Pennsylvania, was recently approved for clinical use by the Food and Drug Administration, representing a landmark in the application of adoptive T cell therapies...
October 16, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/29038795/immune-engineering-from-systems-immunology-to-engineering-immunity
#10
Ning Jiang
The smallpox vaccine represents the earliest attempt in engineering immunity. The recent success of chimeric antigen receptor T cells (CAR-T cells) in cancer once again demonstrates the clinical potential of immune engineering. Inspired by this success, diverse approaches have been used to boost various aspects of immunity: engineering dendritic cells (DCs), natural killer (NK) cells, T cells, antibodies, cytokines, small peptides, and others. With recent development of various high-throughput technologies (of which engineers, especially biomedical engineers/bioengineers contributed significantly), such as immune repertoire sequencing, and analytical methods, a systems level of understanding immunity (or the lack of it) beyond model animals has provided critical insights into the human immune system...
March 2017: Curr Opin Biomed Eng
https://www.readbyqxmd.com/read/29038338/infectious-complications-of-cd19-targeted-chimeric-antigen-receptor-modified-t-cell-immunotherapy
#11
Joshua A Hill, Daniel Li, Kevin A Hay, Margaret L Green, Sindhu Cherian, Xueyan Chen, Stanley R Riddell, David G Maloney, Michael Boeckh, Cameron J Turtle
Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T) cell immunotherapy is a novel treatment for refractory or relapsed B cell malignancies. However, infectious complications of this approach have not been systematically studied. We evaluated infection events occurring between days 0-28 and 29-90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study (https://clinicaltrials.gov/ct2/show/NCT01865617). We used multivariable Poisson and Cox regression to evaluate pre- and post-treatment risk factors for infection, respectively...
October 16, 2017: Blood
https://www.readbyqxmd.com/read/29032736/coccidioidomycosis-immunoglobulin-deficiency-safety-challenges-with-car-t-cells-therapy-for-relapsed-lymphoma
#12
Umar Zahid, Al-Aman Shaukat, Nida Hassan, Faiz Anwer
Treatment of patients with relapsed or refractory lymphoma may require allogenic hematopoietic stem cell transplant (HSCT), but treatment of post-transplant relapse disease remains very challenging. Donor lymphocyte infusion and blinatumomab have been used with limited success for the treatment of relapse. Initial data on donor-derived CAR T cells has shown this modality to be safe and highly effective in various hematological malignancies. We present a case of a patient with highly refractory, transformed follicular lymphoma who failed both autologous and allogenic HSCT...
October 2017: Immunotherapy
https://www.readbyqxmd.com/read/29032733/car-t-cells-and-allogeneic-hematopoietic-stem-cell-transplantation-for-relapsed-refractory-b-cell-acute-lymphoblastic-leukemia
#13
Jun Liu, Xi Zhang, Jiang F Zhong, Cheng Zhang
Relapsed/refractory acute lymphoblastic leukemia (ALL) has a low remission rate after chemotherapy, a high relapse rate and poor long-term survival even when allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed. Chimeric antigen receptors redirected T cells (CAR-T cells) can enhance disease remission with a favorable outcome for relapsed/refractory ALL, though some cases quickly relapsed after CAR-T cell treatment. Thus, treatment with CAR-T cells followed by allo-HSCT may be the best way to treat relapsed/refractory ALL...
October 2017: Immunotherapy
https://www.readbyqxmd.com/read/29032264/building-a-safer-and-faster-car-seatbelts-airbags-and-crispr
#14
REVIEW
Miguel-Angel Perales, Partow Kebriaei, Leslie S Kean, Michel Sadelain
Therapeutic T cell engineering has recently garnered widespread interest owing to the success of CD19 (Chimeric Antigen Receptor) CAR therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and non-Hodgkin lymphoma...
October 12, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29029813/innovative-therapy-monoclonal-antibodies-and-beyond
#15
M Di Nicola, L Apetoh, M Bellone, M P Colombo, G Dotti, S Ferrone, M Muscolini, J Hiscott, A Anichini, S M Pupa, F de Braud, M Del Vecchio
The seventh Edition of "Innovative Therapy, Monoclonal Antibodies and Beyond" Meeting took place in Milan, Italy, on January 27, 2017. The two sessions of the meeting were focused on: 1) Preclinical assays and novel biotargets; and 2) monoclonal antibodies, cell therapies and targeted molecules. Between these two sessions, a lecture entitled "HLA-antigens modulation and response to immune checkpoint inhibitor immunotherapy" was also presented. Despite the impressive successes in cancer immunotherapy in recent years, the response to immune based interventions occurs only in a minority of patients (∼20%)...
October 5, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/29025771/endothelial-activation-and-blood-brain-barrier-disruption-in-neurotoxicity-after-adoptive-immunotherapy-with-cd19-car-t-cells
#16
Juliane Gust, Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, David Myerson, Luis F Gonzalez-Cuyar, Cecilia Yeung, W Conrad Liles, Mark Wurfel, Jose A Lopez, Junmei Chen, Dominic Chung, Susanna Harju-Baker, Tahsin Özpolat, Kathleen R Fink, Stanley R Riddell, David G Maloney, Cameron J Turtle
Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19(+) cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability...
October 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29025766/car-t-therapy-targeting-icam-1-eliminates-advanced-human-thyroid-tumors
#17
Irene M Min, Enda Shevlin, Yogindra Vedvyas, Marjan Zaman, Brian Wyrwas, Theresa Scognamiglio, Maureen D Moore, Weibin Wang, Susan Park, Spencer Park, Suraj Panjwani, Katherine D Gray, Andrew B Tassler, Rasa Zarnegar, Thomas J Fahey, Moonsoo M Jin
PURPOSE: Poorly-differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors including papillary thyroid cancer (PTC) and ATC are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1-targeting agents for the treatment of aggressive cancer. We developed a third-generation CAR targeting ICAM-1 to leverage adoptive T cell therapy as a new treatment modality. EXPERIMENTAL DESIGN: ICAM-1 CAR T cells were applied on multiple malignant and non-malignant target cells to investigate specific target cell death and 'off-tumor' toxicity in vitro...
October 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29025266/the-abcs-of-immunotherapy-for-adult-patients-with-b-cell-acute-lymphoblastic-leukemia
#18
Troy Z Horvat, Amanda N Seddon, Adebayo Ogunniyi, Amber C King, Larry W Buie, Ryan J Daley
OBJECTIVE: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). DATA SOURCES: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR)...
October 1, 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/29024301/emerging-principles-from-the-clinical-application-of-chimeric-antigen-receptor-car-t-cell-therapies-for-b-cell-malignancies
#19
REVIEW
Michael D Jain, Marco L Davila
Gene-engineered T cell therapies are soon to be FDA approved for at least two types of B cell malignancies in pediatric and adult patients, in the form of CD19 targeted chimeric antigen receptor T (CAR T) cell therapy. This represents a triumph of a true bench to bedside clinical translation of a therapy that was conceived of in the early 1990s. Clinical results have demonstrated efficacious responses in patients with the CD19 positive diseases B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B cell lymphoma (DLBCL)...
October 11, 2017: Stem Cells
https://www.readbyqxmd.com/read/29023549/supraphysiologic-control-over-hiv-1-replication-mediated-by-cd8-t-cells-expressing-a-re-engineered-cd4-based-chimeric-antigen-receptor
#20
Rachel S Leibman, Max W Richardson, Christoph T Ellebrecht, Colby R Maldini, Joshua A Glover, Anthony J Secreto, Irina Kulikovskaya, Simon F Lacey, Sarah R Akkina, Yanjie Yi, Farida Shaheen, Jianbin Wang, Keith A Dufendach, Michael C Holmes, Ronald G Collman, Aimee S Payne, James L Riley
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs...
October 2017: PLoS Pathogens
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