Cancer Immunotherapy Review
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Cancer Immunotherapy Review
A magic life saving cure for advanced metastatic melanoma.  
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Ipilimumab (BMS) Review: A Cancer Breakthrough? - un knol de Krishan Maggon

Ipilimumab (BMS) Review: A Cancer Breakthrough? - un knol de Krishan Maggon | Cancer Immunotherapy Review | Scoop.it
FDA has approved Yervoy (ipilimumab, BMS) under REMS for the treatment of metastatic melanoma. The European expert panel CHMP...
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rosywills's comment, September 22, 2017 4:07 AM
Cancer Immunotherapy Market is expected to reach USD 119.39 Billion by 2021
Download Free Brochure @ http://bit.ly/2cHlrFH
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Pancreatic Cancer Clinical Trial with Immunotherapy and Chemotherapy

Pancreatic Cancer Clinical Trial with Immunotherapy and Chemotherapy | Cancer Immunotherapy Review | Scoop.it
Parker Institute study evaluating a CD40 Antibody, Anti-PD-1 Checkpoint Inhibitor and Chemotherapy in Combination...
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MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma

MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma | Cancer Immunotherapy Review | Scoop.it
Imaging tracking of the migration of cell-based drug delivery systems are needed for expanding their clinical application for glioma. Here they report inflammation activatable engineered neutrophils containing doxorubicin-loaded magnetic mesoporous silica nanoparticles to image and actively target...
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Genetically modified T cells target lymphoma

Genetically modified T cells target lymphoma | Cancer Immunotherapy Review | Scoop.it
A therapeutic approach in which a person’s immune cells are genetically recoded to enable them to target their cancerous cousins is helping people whose disease is beyond the reach of existing treatments.
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Pioneering cancer immunotherapy researcher Jim Allison’s path to the Nobel Prize

Pioneering cancer immunotherapy researcher Jim Allison’s path to the Nobel Prize | Cancer Immunotherapy Review | Scoop.it
On the first day of October this year, the first Nobel Prize given for a cancer therapy in 28 years went to the first MD Anderson Cancer Center scientist to receive the world’s most pre-eminent award for outstanding discoveries in life sciences and medicine.
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How can obesity both fuel tumor growth and help new immunotherapy drugs work better?

How can obesity both fuel tumor growth and help new immunotherapy drugs work better? | Cancer Immunotherapy Review | Scoop.it
Two studies have provided new insights into the relationship between obesity and cancer. The research reveals fascinatingly paradoxical effects, suggesting obesity can suppress our immune responses to enhance tumor growth, but also improve the efficacy of a new kind of cancer-killing immunotherapy.
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Support Cancer Immunotherapy research

Support Cancer Immunotherapy research | Cancer Immunotherapy Review | Scoop.it
ACIR.org prepares a free weekly digest of the key advances in the field of cancer immunotherapy. This valuable and much needed resource allows scientists to spend more time on their research and hopefully find a cure.
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VISTA expressed in tumour cells regulates T cell function

VISTA expressed in tumour cells regulates T cell function | Cancer Immunotherapy Review | Scoop.it

Background

V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune-checkpoint protein. VISTA expression on tumour cells and the associated regulatory mechanisms remain unclear. We investigated VISTA expression and function in tumour cells, and evaluated its mechanism and activity.

Methods

VISTA in tumour cells was assessed by tissue microarray analysis, immunohistochemical staining and western blot. A series of in vitro assays were used to determine the function of tumour-expressed VISTA. In vivo efficacy was evaluated in syngeneic models.

Results

VISTA was highly expressed in human ovarian and endometrial cancers. Upregulation of VISTA in endometrial cancer was related to the methylation status of the VISTA promoter. VISTA in tumour cells suppressed T cell proliferation and cytokine production in vitro, and decreased the tumour-infiltrating CD8+ T cells in vivo. Anti-VISTA antibody prolonged the survival of tumour-bearing mice.

Conclusions

This is the first demonstration that VISTA is highly expressed in human ovarian and endometrial cancer cells, and that anti-VISTA antibody treatment significantly prolongs the survival of mice bearing tumours expressing high levels of VISTA. The data suggest that VISTA is a novel immunosuppressive factor within the tumour microenvironment, as well as a new target for cancer immunotherapy.

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AMSBIO Launch PD-L2 Activator Cell Line for Immune Checkpoint Therapy Research

AMSBIO has added an important new product to its immunotherapy range - a PD-L2 / TCR activator - CHO Recombinant Cell Line...
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Paper: Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Mult...

Paper: Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Mult... | Cancer Immunotherapy Review | Scoop.it
LCAR-B38M is a bispecific chimeric antigen receptor T cell (CAR T) therapy directed against B-cell maturation antigen (BCMA). The bi-epitope BCMA binding moieties confer high avidity binding and distinguish LCAR-B38M from other BCMA CAR constructs. Preliminary results of LCAR-B38M in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM) showed encouraging efficacy and manageable safety (Fan et al. JCO 2017;35:18_suppl LBA3001). Here we present updated safety and efficacy results of the trial. LEGEND-2 (NCT03090659) is an ongoing phase 1, single-arm, open-label multicenter study evaluating LCAR-B38M in pts (18–80 years) with R/R MM. Lymphodepletion was performed using 3 doses of cyclophosphamide 300 mg/m2 on days -5, -4, and -3. Five days after lymphodepletion, LCAR-B38M CAR T cells (median CAR+ cell dose = 0.5x106 cells/kg, [range, 0.07–2x106]) were given in 3 infusions (20, 30, and 50% of total dose). The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the anti-myeloma response of the treatment. Adverse events (AEs) were graded using the Common Terminology Criteria for AE, v.4.03, and cytokine release syndrome (CRS) was assessed according to Lee et al. (Blood 2014;124:188-95). Response was evaluated using International Myeloma Working Group criteria. This analysis presents data from a single institution. As of June 25, 2018, 57 pts have been infused with LCAR-B38M CAR T cells. The median age was 54 years (range, 27–72), median number of prior therapies was 3 (range, 1–9), and 74% of pts had stage III disease by Durie-Salmon staging. The median duration of follow-up for all pts was 12 months (range, 0.7–25). AEs were reported by all pts; most common were pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts; most common were leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%). CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 cases. Liver function abnormalities were the most common signs of end organ injury among pts with CRS. The median time to onset of CRS was 9 days (range, 1–19). All but 1 CRS events resolved, with a median duration of 9 days (range, 3–57). No clear relationship was demonstrated between dose and CRS; there may be some effect at higher doses, but conclusions are limited by the small number of pts in the grade 3 CRS group (n=4; Figure 1A). Neurotoxicity was observed in 1 pt who had grade 1 aphasia, agitation, and seizure-like activity. The overall response rate (partial response [PR] or better) was 88% (95% confidence interval [CI], 76–95). Complete response (CR) was achieved by 42 pts (74%; 95% CI, 60–85), very good partial response was achieved by 2 pts (4%; 95% CI, 0.4–12), and PR was achieved by 6 pts (11%; 95% CI, 4–22; Figure 1B). Among pts with CR, 39/42 were minimal residual disease (MRD) negative by 8-color flow cytometry. The median time to initial response was 1 month (range, 0.4–4). No clear relationship between LCAR-B38M CAR T cell dose and response was observed (Figure 1C). BCMA expression did not correlate with clinical response. The median duration of response (DOR) was 16 months (95% CI, 12–not reached [NR]). The median DOR for pts who achieved a CR was 22 months (95% CI, 14–NR). At data cutoff, 18 pts (36%) who achieved PR or better progressed. The median progression-free survival (PFS) for all treated pts was 15 months (95% CI, 11–NR); median PFS for pts who achieved CR was 24 months (95% CI, 15–NR)­. The median overall survival was not reached. Overall, 17 pts died during the study and follow-up period; causes of death were progressive disease (PD; n=14), suicide after PD (n=1), esophagitis (n=1), and pulmonary embolism and acute coronary syndrome (n=1). Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M CAR T cells were not detectable in peripheral blood in 71% of pts at 4 months; 5 pts showed CAR T cell persistence up to 10 months. This ongoing first-in-human study has provided initial proof-of-concept that bispecific LCAR‑B38M CAR T cells may be a highly effective therapy for R/R MM. LCAR-B38M CAR T cell therapy displayed a manageable safety profile consistent with its known mechanism of action and demonstrated deep and durable responses in pts with R/R MM. A phase 1/2 study of LCAR-B38M in R/R MM has been initiated in the US (NCT03548207).
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Paper: Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed/Refractory (r/r) Acute Lymphoblastic Leukemia

Paper: Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed/Refractory (r/r) Acute Lymphoblastic Leukemia | Cancer Immunotherapy Review | Scoop.it
Program: Oral and Poster Abstracts Type: Oral Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Improving Outcomes with Cellular Therapy Hematology Disease Topics & Pathways: Biological, Therapies, CAR-Ts Monday, December 3, 2018: 4:30 PM Room 6A (San Diego Convention Center) Stephan A. Grupp, MD, PhD1,2, Shannon L. Maude, MD, PhD1,2, Susana Rives3*, Andre Baruchel, MD4, Michael W. Boyer, MD5, Henrique Bittencourt, MD, PhD6,7,8*, Peter Bader, MD, PhD9, Jochen Büchner, MD, PhD10*, Theodore W. Laetsch, MD11,12*, Heather Stefanski, MD, PhD13, Gary Douglas Myers, MD14*, Muna Qayed, MD, MSc15, Michael A. Pulsipher, MD16, Barbara De Moerloose, MD, PhD17,18*, Gregory A. Yanik, MD19*, Kara L. Davis, DO20, Paul L. Martin, MD, PhD21, Eneida R. Nemecek, MD22, Christina Peters, MD23*, Joerg Krueger, MD24*, Adriana Balduzzi, MD25, Nicolas Boissel, Md, PhD26*, Francoise Marie Mechinaud, MD, FRACP27*, Mimi Leung28*, Lamis K. Eldjerou, MD28, Lan Yi, PhD28*, Karen Thudium Mueller, PharmD, MSc29*, Eric Bleickardt, MD28* and Hidefumi Hiramatsu, M.D., Ph.D.30 1Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 2Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA 3Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu de Barcelona, Barcelona, ESP 4Pediatric Hematology and Immunology Department, Robert Debre Hospital, APHP, Paris, France 5Department of Pediatrics and Internal Medicine, University of Utah, Salt Lake City, UT 6Hematology Oncology Division, CHU Sainte-Justine, Montreal, Canada 7Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Canada 8Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Canada 9Hospital for Children and Adolescents; Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt, Germany 10Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway 11Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 12Pauline Allen Gill Center for Cancer and Blood Disorders, Children’s Health, Dallas, TX 13Department of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN 14Children’s Mercy Hospital, Kansas City, MO 15Emory University, Atlanta, GA 16Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 17Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium 18Cancer Research Institute Ghent (CRIG), Ghent, Belgium 19C.S. Mott Children’s Hospital, Ann Arbor, MI 20Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 21Division of Pediatric Blood and Marrow Transplant, Duke University Medical Center, Durham, NC 22Pediatric Hematology/Oncology & Bone Marrow Transplantation, Oregon Health & Science University, Portland, OR 23Stem Cell Transplantation Unit, St. Anna Children's Hospital, Vienna, Austria 24Department of Translational Oncology, Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada 25Clinica Pediatrica Università degli Studi di Milano Bicocca, Monza, Italy 26Hopital Saint-Louis-University, Paris, France 27Children's Cancer Centre, The Royal Children's Hospital Melbourne, Melbourne, Australia 28Novartis Pharmaceuticals Corporation, East Hanover, NJ 29Novartis Institutes for BioMedical Research, East Hanover, NJ 30Department of Pediatrics, Graduate School of Medicine Kyoto University, Kyoto, Japan BACKGROUND Tisagenlecleucel is an FDA approved chimeric antigen receptor (CAR)-T cell therapy that reprograms T cells to eliminate CD19+ B cells. ELIANA (NCT02435849) is a phase 2 pivotal study of tisagenlecleucel in pediatric/young adult patients (pts) with CD19+ r/r B-cell acute lymphoblastic leukemia (ALL), the first global trial of a CAR-T cell therapy. The primary objective was met, with an overall remission rate (ORR) of 81% (complete remission [CR] + CR with incomplete blood count recovery [CRi]). Here we present an update of ELIANA, with additional pts and additional 11 mo follow-up from the previous report (Maude et al. N Engl J Med 2018). METHODS Eligible pts were aged ≥3 y at screening and ≤21 y at diagnosis and had ≥5% leukemic blasts in bone marrow. Tisagenlecleucel was centrally manufactured at 2 sites (Morris Plains, NJ, USA and Leipzig, Germany) by lentiviral transduction of autologous T cells with a vector encoding for a second generation 4-1BB anti-CD19 CAR and expanded ex vivo. Tisagenlecleucel was provided to pts at 25 study centers in 11 countries on 4 continents using cryopreserved apheresed mononuclear cells, central production facilities, and a global supply chain. The primary endpoint, ORR within 3 mo and maintained for ≥28 d among infused pts, was assessed by an independent review committee. Secondary endpoints included duration of remission (DOR), overall survival (OS), safety, and cellular kinetics. RESULTS As of April 13, 2018, 113 pts were screened and 97 enrolled. There were 8 manufacturing failures (8%) and 10 pts (10%) were not infused due to death or adverse events (AEs). Following lymphodepleting chemotherapy in most pts (76/79; fludarabine/cyclophosphamide [n=75]), 79 pts were infused with a single dose of tisagenlecleucel (median dose, 3.0×106 [range, 0.2-5.4×106] CAR-positive viable T cells/kg), and all had ≥3 mo of follow-up or discontinued earlier (median time from infusion to data cutoff, 24 mo [range, 4.5-35 mo]). Median age was 11 y (range, 3-24 y); 61% of pts had prior hematopoietic stem cell transplant (SCT). Among the 65 pts with CR/CRi, 64 (98%) were MRD– within 3 mo. Median DOR by K-M analysis was not reached (Figure): responses were ongoing in 29 pts (max DOR, 29 mo and ongoing); 19 pts relapsed before receiving additional anticancer therapy (13 died subsequently); 8 pts underwent SCT while in remission, 8 received additional anticancer therapy (non-SCT) and 1 discontinued while in remission. The probability of relapse-free survival at 18 mo was 66% (95% CI, 52%-77%). Median OS was not reached; OS probability at 18 mo was 70% (95% CI, 58%-79%). Cytokine release syndrome (CRS) occurred in 77% of pts (grade [G] 3/4; 48%; graded using the Penn scale); 39% of pts received tocilizumab for treatment of CRS with or without other anti-cytokine therapies; 48% of pts required ICU-level care for CRS, with a median ICU stay of 7 d. All cases of CRS were reversible. Most common G 3/4 nonhematologic AEs (>15%) other than CRS were neutropenia with a body temperature >38.3°C (62% within 8 wk of infusion), hypoxia (20%), and hypotension (20%). 13% of pts experienced G 3 neurological events, with no G 4 events or cerebral edema. Based on laboratory results, 43% and 54% of pts had G 3/4 thrombocytopenia and neutropenia not resolved by d 28; the majority of events resolved to G ≤2 by 3 mo. 25 post-infusion deaths were reported: 2 within 30 d (1 disease progression, 1 cerebral hemorrhage); 23 after 30 d of infusion (range, 53-859 d; 18 disease progression, 1 each due to encephalitis, systemic mycosis, VOD [hepatobiliary disorders related to allogeneic-SCT], bacterial lung infection, and an unknown reason after study withdrawal). Tisagenlecleucel expansion in vivo correlated with CRS severity, and persistence of tisagenlecleucel along with B-cell aplasia in peripheral blood was observed for ≥2.5 y in some responding pts. Analysis of B-cell recovery and correlation with relapse will be presented. CONCLUSIONS With longer follow-up, the ELIANA study continues to confirm the efficacy of a single infusion of tisagenlecleucel in pediatric and young adults with ALL without additional therapy. AEs were effectively and reproducibly managed globally by appropriately trained personnel at study sites. The achievement of high overall response rates and deep remissions, in combination with the median duration of response and overall survival not being reached, further corroborate previously reported results. Disclosures: Grupp: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude: Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rives: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation for medical congresses, Speakers Bureau; Servier: Honoraria, Other: Travel and accommodation for medical congresses, Speakers Bureau; Shire: Honoraria, Other: Travel and accommodation for medical congresses, Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel and accommodation for medical congresses, Speakers Bureau; Baxalta: Honoraria, Other: Travel and accommodation for medical congresses, Speakers Bureau; Amgen: Other: Travel and accommodation for medical congresses, Speakers Bureau; Erytech Pharma: Other: Travel and accommodation for medical congresses, Speakers Bureau. Baruchel: Celgene: Consultancy; Amgen: Consultancy; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Novartis: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Servier: Consultancy. Bittencourt: Novartis Pharmaceuticals Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria. Bader: Riemser: Research Funding; Cellgene: Consultancy; Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Novartis: Consultancy, Speakers Bureau. Laetsch: Bayer: Consultancy; Pfizer: Equity Ownership; Eli Lilly: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Loxo Oncology: Consultancy. Stefanski: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Speakers Bureau. Myers: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Qayed: Novartis: Consultancy. Pulsipher: CSL Behring: Consultancy; Amgen: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding. Martin: Novartis Pharmaceuticals Corporation: Research Funding; Jazz Pharmaceuticals: Research Funding. Nemecek: Novartis Pharmaceuticals Corporation: Other: advisory boards. Boissel: Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leung: Novartis Pharmaceuticals Corporation: Employment. Eldjerou: Novartis Pharmaceuticals Corporation: Employment. Yi: Novartis Pharmaceuticals Corporation: Employment. Mueller: Novartis Institutes for Biomedical Research: Employment; Novartis Pharmaceuticals Corporation: Equity Ownership, Other: Patent pending. Bleickardt: Novartis Pharmaceuticals Corporation: Employment. See more of: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Improving Outcomes with Cellular Therapy See more of: Oral and Poster Abstracts Previous Abstract | Next Abstract >> *signifies non-member of ASH
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Global Immuno-Oncology Landscape Analysis Update Published in Nature Reviews Drug Discovery - News from the

Global Immuno-Oncology Landscape Analysis Update Published in Nature Reviews Drug Discovery - News from the | Cancer Immunotherapy Review | Scoop.it
The Cancer Research Institute has released an update to its global immuno-oncology landscape analysis, published today in Nature Reviews Drug Discovery...
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Wallchart Request Nature Protocols CAR T Cells

Wallchart Request Nature Protocols CAR T Cells | Cancer Immunotherapy Review | Scoop.it
Receive a free wallchart on ‘Production of CAR T Cells”, produced by Nature protocols and Supported by STEMCELL Technologies.
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Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials | Clinical and Translational Medicine 

Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials | Clinical and Translational Medicine  | Cancer Immunotherapy Review | Scoop.it
Advances in the understanding of cancer immunotherapy and the development of multiple checkpoint inhibitors have dramatically changed the current landscape of cancer treatment. Recent large-scale phase III trials (e.g. PHOCUS, OPTiM) are establishing use of oncolytic viruses as another tool in the cancer therapeutics armamentarium. These viruses do not simply lyse cells to achieve their cancer-killing effects, but also cause dramatic changes in the tumor immune microenvironment. This review will highlight the major vector platforms that are currently in development (including adenoviruses, reoviruses, vaccinia viruses, herpesviruses, and coxsackieviruses) and how they are combined with checkpoint inhibitors. These vectors employ a variety of engineered capsid modifications to enhance infectivity, genome deletions or promoter elements to confer selective replication, and encode a variety of transgenes to enhance anti-tumor or immunogenic effects. Pre-clinical and clinical data have shown that oncolytic vectors can induce anti-tumor immunity and markedly increase immune cell infiltration (including cytotoxic CD8+ T cells) into the local tumor microenvironment. This “priming” by the viral infection can change a ‘cold’ tumor microenvironment into a ‘hot’ one with the influx of a multitude of immune cells and cytokines. This alteration sets the stage for subsequent checkpoint inhibitor delivery, as they are most effective in an environment with a large lymphocytic infiltrate. There are multiple ongoing clinical trials that are currently combining oncolytic viruses with checkpoint inhibitors (e.g. CAPTIVE, CAPRA, and Masterkey-265), and the initial results are encouraging. It is clear that oncolytic viruses and checkpoint inhibitors will continue to evolve together as a combination therapy for multiple types of cancers.

Keywords
Immune checkpoint inhibitors
Oncolytic viral therapy
Clinical trials
Immunotherapy
Combination therapy
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ESMO | 2018 Immuno-Oncology Award | ESMO

ESMO | 2018 Immuno-Oncology Award | ESMO | Cancer Immunotherapy Review | Scoop.it
ESMO selected Cornelis Melief to receive 2018 ESMO Immuno-Oncology Award for his life’s work in studying interactions of the immune system with cancer...
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Building a better lymphoma vaccine

Building a better lymphoma vaccine | Cancer Immunotherapy Review | Scoop.it
Researchers are closing in on vaccines to prevent or treat lymphomas and other cancers triggered by the Epstein–Barr virus.
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Geneius Biotech Targeted DiversiTy™ T cell Therapies

Geneius Biotech Targeted DiversiTy™ T cell Therapies | Cancer Immunotherapy Review | Scoop.it

Geneius is developing an autologous, adoptive cell therapy technology which is designed to selectively unleash the patient’s immune response to cancer.  Geneius’ Targeted DiversiTy™ platform re-educates the patient’s own T cells to be responsive to overlooked antigens to deliver a specific and durable immune response that we believe is less susceptible to tumor immune evasion. 

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ESMO 2018 | Renal cell carcinoma trial analysis: current landscape of immunotherapy combinations

ESMO 2018 | Renal cell carcinoma trial analysis: current landscape of immunotherapy combinations | Cancer Immunotherapy Review | Scoop.it
Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, MA, discusses various immunotherapy combinations showing promising results in early and late stage clinical trials for advanced renal cell carcinoma.
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PD-Loma: a cancer entity with a shared sensitivity to the PD-1/PD-L1 pathway blockade

PD-Loma: a cancer entity with a shared sensitivity to the PD-1/PD-L1 pathway blockade | Cancer Immunotherapy Review | Scoop.it
Editorial

 

Clinical trials have now identified over 30 cancer histotypes with sensitivity to anti-PD-(L)1 therapies. It is the first time in oncology that a class of drugs has demonstrated such a wide spectrum of activity in monotherapy. This subgroup of cancers (‘PD-Lomas’) is driving the clinical research strategies for the next generation of combination immunotherapy.

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Inflammation-induced Id2 promotes plasticity in regulatory T cells

Inflammation-induced Id2 promotes plasticity in regulatory T cells | Cancer Immunotherapy Review | Scoop.it
TH17 cells originating from regulatory T (Treg) cells upon loss of the Treg-specific transcription factor Foxp3 accumulate in sites of inflammation and aggravate autoimmune diseases. Whether an active mechanism drives the generation of these pathogenic ‘ex-Foxp3 TH17’ cells, remains unclear. Here we show that pro-inflammatory cytokines enhance the expression of transcription regulator Id2, which mediates cellular plasticity of Treg into ex-Foxp3 TH17 cells. Expression of Id2 in in vitro differentiated iTreg cells reduces the expression of Foxp3 by sequestration of the transcription activator E2A, leading to the induction of TH17-related cytokines. Treg-specific ectopic expression of Id2 in mice significantly reduces the Treg compartment and causes immune dysregulation. Cellular fate-mapping experiments reveal enhanced Treg plasticity compared to wild-type, resulting in exacerbated experimental autoimmune encephalomyelitis pathogenesis or enhanced anti-tumor immunity. Our findings suggest that controlling Id2 expression may provide a novel approach for effective Treg cell immunotherapies for both autoimmunity and cancer.
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Tumour immune cells could aid cancer therapies, study shows

Tumour immune cells could aid cancer therapies, study shows | Cancer Immunotherapy Review | Scoop.it
A pioneering technique designed to spot differences between immune cells in tumours could speed the development of cancer treatments, research suggests.
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JCI - An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion

JCI - An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion | Cancer Immunotherapy Review | Scoop.it
Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and a large fraction of patients with the responsive types of cancers do not respond to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints exist. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation and allograft tumor tolerance. However, analysis of chimera mice with competitive reconstitution of WT and IRF8-KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in CD11b+Ly6CloLy6G+ myeloid cells and OPN acted as a potent T cell suppressor. IRF8 bound to the Spp1 promoter to repress OPN expression in colon epithelial cells, and colon carcinoma exhibited decreased IRF8 and increased OPN expression. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicate that myeloid and tumor cell–expressed OPN acts as an immune checkpoint to suppress T cell activation and confer host tumor immune tolerance.
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Lilly, NextCure Launch Cancer Immunotherapy Partnership

Lilly, NextCure Launch Cancer Immunotherapy Partnership | Cancer Immunotherapy Review | Scoop.it
Eli Lilly will use NextCure’s Functional, Integrated, NextCure Discovery in Immuno Oncology (FIND-IO™) platform to discover and develop cancer targets for new immuno-oncology therapies, the companies said, through a collaboration set to generate more than $40 million for the Beltsville, MD, cancer...
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Paper: Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma

Paper: Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma | Cancer Immunotherapy Review | Scoop.it
Program: Oral and Poster Abstracts Type: Oral Session: 627. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Retrospective/Observational Studies: Outcomes With CD19 CAR T Therapy and Checkpoint Blockade in the Real World Setting Hematology Disease Topics & Pathways: Biological, Diseases, Therapies, Lymphoma (any), CAR-Ts, Elderly, DLBCL, Study Population, Lymphoid Malignancies Saturday, December 1, 2018: 10:45 AM Pacific Ballroom 20 (Marriott Marquis San Diego Marina) Dahlia Sano, MBBCH1, Loretta J. Nastoupil, MD2, Nathan H. Fowler, MD3, Luis Fayad, MD4, F. B. Hagemeister, MD5, Hun Ju Lee, MD6, Felipe Samaniego, MD6, Michael Wang, MD7, Maria Alma Rodriguez, MD8*, Swaminathan P Iyer, MD9, Simrit Parmar, MBBS6, Raphael Steiner, MD10, Ranjit Nair, MBBS, MD2, Sherry Adkins, ANP11*, Sara Arafat, M.D12*, Ahalya Rao, MD13*, Liliana Vallejo14*, Misha Hawkins15*, Yiming Chen16*, Jason R. Westin, MD5 and Sattva S. Neelapu, MD17,18 1Md Anderson Cancer Center, Houston 2The University of Texas MD Anderson Cancer Center, Houston, TX 3Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 4MD Anderson Cancer Center, Houston, TX 5Department of Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, TX 6Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 7Department of Lymphoma and Myeloma, U.T. M.D. Anderson Cancer Center, Houston, TX 8M.D. Anderson Cancer Ctr. University of Texas, Houston, TX 9Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX 10Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 11MD Anderson cancer center, Houston, TX 12Md Anderson cancer center, Md Anderson Cancer Center, Houston, TX 13MD ANDERSON, Houston, TX 14Md Anderson cancer center, Houston 15Md Amderson cancer Center, Houston 16Md Anderson cancer Center, Houston 17Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston, TX 18Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients <65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were <65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger (<65 years) patients with relapsed or refractory large B-cell lymphoma. Disclosures: Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler: Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego: ADC Therapeutics: Research Funding. Wang: Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin: Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. See more of: 627. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Retrospective/Observational Studies: Outcomes With CD19 CAR T Therapy and Checkpoint Blockade in the Real World Setting See more of: Oral and Poster Abstracts << Previous Abstract | Next Abstract *signifies non-member of ASH
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Radical optimism: considering the future of immunotherapy

Radical optimism: considering the future of immunotherapy | Cancer Immunotherapy Review | Scoop.it
I wrote recently about the sense of angst taking hold in the next-generation class of immuno-therapeutics - those targets that have come after the anti-CTLA4 and anti-PD-(L)-1 classes, and raised the hope that combination immunotherapy would broadly raise response rates and durabi...
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Paper: CD38 Specific Chimeric Antigen Receptor KHYG-1 Natural Killer Cells: A Potential “Off the Shelf” Therapy for Multiple Myeloma

Paper: CD38 Specific Chimeric Antigen Receptor KHYG-1 Natural Killer Cells: A Potential “Off the Shelf” Therapy for Multiple Myeloma | Cancer Immunotherapy Review | Scoop.it
Chimeric Antigen Receptors (CARs) are engineered transmembrane proteins consisting of an antibody-derived antigen recognition domain linked to intracellular cell signaling domains. CAR engineered autologous T cells have been successful in the treatment of a variety of hematologic malignancies. However, several major caveats, including lack of universal donors, long manufacturing times, and absence of a donor in immunologically frail patients, have limited the successful translation of CAR-T cell based therapy to a larger pool of patients. A universal, easy to manufacture, “off the shelf” CAR-based product could potentially address these limitations and result in a lower cost of goods. Towards developing an “off the shelf” CAR-based therapy for Multiple Myeloma (MM), we explored the feasibility and preclinical efficacy of expressing CD38 CARs in KHYG-1 cells, a natural killer (NK) cell line, first established by Yagita et al from a patient with aggressive NK leukemia (Leukemia, 2000). To this end, we effectively transduced KHYG-1 cells with high-affinity CD38 CARs as well as our recently reported affinity-optimized CD38 CARs, which can readily target MM cells with high CD38 expression, while ignoring non-malignant cells with intermediate, low or no CD38 expression when brought to expression on T cells (Drent et al, Molecular Therapy 2017). Moreover, we assessed performance of first and second generation CARs, with co-stimulatory domains CD28 and 4-1BB, and found the combination of CD28/CD3ζ to lead to the best results. After expanding the CAR transduced KHYG-1 cells, we analyzed their phenotype and efficacy in MM by analyzing their cytotoxic activity against CD38+ and CD38- MM and AML cell lines (UM9/THP-1 and U266/HL60, respectively), and against primary MM cells. The CD38-CAR transduced KHYG-1 cells showed no phenotypic alterations, and at effector to target ratios as low as 1:1, induced a high cytotoxicity towards CD38+ cell lines as compared to mock or non-transduced KHYG-1, demonstrating the important contribution of the CD38 CAR on the KHYG-1 NK cell surface. CD38- cell lines were unaffected by both CD38-CAR transduced KHYG-1 cells and mock or non-transduced KHYG-1 cells, indicating the specificity towards CD38 of the CAR and thus the potential safety of the CD38-CAR KHYG-1 cell. Similarly, ex vivo assays using primary MM cells revealed superior cytotoxic activity of CD38-CAR KHYG-1 cells as compared to mock or non-transduced KHYG-1 cells (median 86,5% vs 14% at 1:1 E:T ratio, n=2, Figure 1A). Confirming our previous results we identified an affinity-optimized CD38-CAR which mediated strong primary MM cell cytotoxicity with little or no “off tumor” effect. Normal immune cells (B, T, monocytes), which were either CD38 negative or only intermediate positive, were unaffected (Figure 1B-D), suggesting the potential safety of the CAR-NK cell therapy for clinical applications. As clinical administration would require irradiation of CD38-CAR KHYG-1 cells, we tested the effect of irradiation on their proliferative and cytotoxicity potential. Irradiation with 10Gy, while drastically inhibiting proliferative activity and viability (50% survival after 3 days), did not affect cytotoxicity, suggesting that repeated administrations of irradiated, CD38-CAR transduced KYHG-1 cells may exert effective in vivo anti-tumor activity, which is currently being evaluated in appropriate in vivo models, specifically the humanized bone scaffold in vivo model published by Groen et al (Blood, 2012). In conclusion, we demonstrate that the incorporation of CAR technology into the immortal NK cell line KHYG-1 has enormous potential to become a safe and effective “off the shelf” therapy for MM.
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