- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS
PD-1 inhibition can be combined with IL-12 in subjects with recurrent glioblastoma (Ballroom Lawn) - Oct 29, 2019 - Abstract #SNO2019SNO_967;
P1
Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a novel gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (V, 20 mg) acting via the proprietary RheoSwitch Therapeutic System® (RTS®), was shown in a phase 1 Main study (NCT02026271) to elicit a sustained intra-tumoral activated cytotoxic T-cell response with co-expression of PD-1...In the first two cohorts (where data is available), combination therapy improved the biomarker “cytoindex” (ratio of circulating CD8+ T cells to FoxP3+ regulatory T cells)...Controlled IL-12 production using Ad+V with nivolumab is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile. Further phase 2 investigation of Ad+V plus a checkpoint inhibitor in rGBM is planned.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Daiichi Sankyo
Clinical Features of CAR T-cell Therapy Neurotoxicity as Potential Surrogate Markers for Progression and Outcome (Ballroom Lawn) - Oct 29, 2019 - Abstract #SNO2019SNO_529;
CONCLUSION Depression, tremor, delirium, encephalopathy, and EEG features of FIRDA and triphasic waves may represent early clinical signs that predict the development of severe NT in off-protocol CAR T-cell therapy. Paradoxically, severe NT is positively correlated with progression free survival and may indicate effective therapeutic response.
- |||||||||| Ad-RTS-hIL-12 / Ziopharm, Intrexon, veledimex (INXN-1001) / Ziopharm
Survival of subjects with recurrent glioblastoma receiving intra-tumoral administration of IL-12 managed with low-dose dexamethasone (Ballroom Lawn) - Oct 29, 2019 - Abstract #SNO2019SNO_353;
P1
Ad-RTS-hIL-12 (Ad) is a novel gene therapy, conditionally expressing IL-12 via the RheoSwitch Therapeutic System® (RTS®) gene switch under control of an oral activator ligand, veledimex (V)...The mechanism of action of Ad+V is based on controlled secretion of recombinant IL-12 (measured in peripheral blood as a surrogate for intra-tumor-production), downstream upregulation of endogenous IFN-g (measured in peripheral blood), and an increase in the “cytoindex” (ratio of circulating CD8+ T cells to FoxP3+ regulatory T cells), an emerging biomarker of overall survival...As of 04Jun19, mOS in the Expansion substudy had not yet been reached (patient enrollment occurred from September 2018-February 2019). Most subjects (65%) received low-dose dexamethasone (cumulative ≤20mg Days 0-14); initial impact of this and other subject characteristics on survival will be presented.
- |||||||||| lisocabtagene maraleucel (JCAR017) / Celgene, Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Daiichi Sankyo
Journal, CAR T-Cell Therapy: Chimeric antigen receptor T-cell therapy for hematological malignancies (Pubmed Central) - Oct 28, 2019
Moreover, CAR T-cell therapies for acute myeloid leukemia (AML), T-cell leukemia, and multiple myeloma are still under development. Our group is currently preparing a phase I study on granulocyte macrophage colony-stimulating factor receptor-targeted CAR T cells in pediatric and adult patients with AML.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis
Review, Journal, CAR T-Cell Therapy: Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. (Pubmed Central) - Oct 24, 2019
Our group is currently preparing a phase I study on granulocyte macrophage colony-stimulating factor receptor-targeted CAR T cells in pediatric and adult patients with AML. We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Daiichi Sankyo
Journal, CAR T-Cell Therapy: Advances in Chimeric Antigen Receptor (CAR)-T Cell Therapies for Solid Tumors. (Pubmed Central) - Oct 18, 2019
This approval marked a major milestone in the use of antigen-directed 'living drugs' for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted. This state-of-the-art review will focus on the challenges, advances, and novel approaches being utilized to implement CAR-T cell immunotherapy for the treatment of solid tumors.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Daiichi Sankyo
Clinical, Review, Journal: Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance. (Pubmed Central) - Oct 16, 2019
Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Clinical, Journal: Progress and Innovations in the Management of Adult Acute Lymphoblastic Leukemia. (Pubmed Central) - Oct 11, 2019
The incorporation of new monoclonal antibodies and other targeted approaches into frontline regimens is showing promising results. If confirmed, such strategies may increase the cure rates in adults to levels achieved in pediatric ALL and reduce the need for intensive and prolonged chemotherapy.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Daiichi Sankyo
Review, Journal, HEOR, CAR T-Cell Therapy: Is it a Chimera? A systematic review of the economic evaluations of CAR-T cell therapy. (Pubmed Central) - Oct 8, 2019
Nevertheless, their budget impact is of overriding importance and it should be incorporated in any economic evaluation. Moreover, more affirmative clinical data are imperative in order to mitigate uncertainty.
- |||||||||| HEOR: So you really think that the cost of drug development drives prices? Then why are every NIH funded treatment so extremely expensive? (Gleevec, Zolgensma, Spinraza, Kymriah, Yescarta, Luxturna, Xtandi, Fabrazyme, etc, etc). (Twitter) - Oct 6, 2019
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis
Trial primary completion date: JULIET: Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (clinicaltrials.gov) - Oct 3, 2019
P2, N=115, Active, not recruiting,
Researchers should refuse to participate in questionable "pediatric" studies. Trial primary completion date: Mar 2017 --> Feb 2023
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Rituxan (rituximab) / Roche, Biogen
BELINDA : A phase 3 study evaluating the safety and efficacy of tisagenlecleucel versus standard of care in adult patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (Prince George's Exhibition Halls AB) - Oct 2, 2019 - Abstract #SITC2019SITC_763;
P3
Eligible patients are aged >=18 years, have histologically confirmed aggressive B-cell NHL relapsed/refractory to frontline therapy containing rituximab and anthracycline within one year of last dose, and are eligible for auto-HSCT...If patients become ineligible for auto-HSCT, patients may receive ibrutinib or lenalidomide at investigators' discretion; upon confirmation of SD/PD by BIRC at or after 12 weeks, patients may crossover to Arm A. The primary outcome is event-free survival (EFS), defined as the time from randomization to the first documented SD/PD at or after 12 weeks (+-1 week), as assessed by BIRC per Lugano criteria, or death at any time... NA
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Daiichi Sankyo
CAR-T nursing education at a UK specialist cancer hospital (Poster Area (Hall 4)) - Oct 2, 2019 - Abstract #ESMO2019ESMO_4698;
The role of a Lecturer Practitioner in CAR-T at a specialist cancer hospital has been created to address some of the educational needs of the nursing and multi-professional team. The post holder is involved in a wide range of educational initiatives, from national bespoke study days and academic cancer care modules to ward based teaching.
- |||||||||| Actemra IV (tocilizumab) / Roche, JW Pharma
Improvement of the prediction of cytokine release syndrome (CRS) in patients with CAR-T therapy (M8) - Sep 30, 2019 - Abstract #DGHO2019DGHO_1344;
These preliminary results suggest that residual lymphoma/leukemia burden and early increase of Kymriah ® -specific TCR in PB and of IL-6 serum levels may identify patients at increased risk of CRS. We will continue this diagnostic program in subsequent CAR-T recipients to optimize in- and outpatient management.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Daiichi Sankyo
Side effects management in CAR-T-cell therapy (R10) - Sep 30, 2019 - Abstract #DGHO2019DGHO_594;
Tisagenlecleucel (Kymriah ®) is approved for patients up to 25 years of age with B cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse as well as for adult patients with DLBCL after two or more lines of systemic therapy...This talk will give an overview on the definitions, diagnostics, grading and management of CAR T cell associated side effects and toxicities. Focusing on current management algorithms as well as supportive therapeutic approaches this talk aims to guide the way in daily practice of clinicians treating their patients with CAR T cells.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Rituxan (rituximab) / Roche, Biogen
BELINDA: A Phase 3 Study Evaluating the Safety and Efficacy of Tisagenlecleucel versus Standard of Care in Adult Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (Cellular Therapy) - Sep 26, 2019 - Abstract #SOHO2019SOHO_466;
P3
For patients (Arm B) with stable disease/progressive disease (SD/PD) at 6 weeks, therapy will be changed to other recommended therapies and, if ineligible for HSCT, patients will receive ibrutinib or lenalidomide at investigators’ discretion; upon confirmation of SD/PD by blinded independent review committee (BIRC) at or after 12 weeks, patients may crossover to Arm A.Main Outcomes Measures The primary outcome is event-free survival (EFS), defined as the time from randomization to the first documented SD/PD at or after 12 weeks (±1 week), as assessed by BIRC per Lugano criteria, or death at any time. Secondary outcomes include EFS as assessed by local investigator, overall survival, overall response rate, duration of response, patient-reported outcomes, safety, and cellular kinetics.
- |||||||||| cyclophosphamide intravenous / generics
The Future of Cellular Therapy () - Sep 26, 2019 - Abstract #SOHO2019SOHO_282;
P1
CAR-T Cells for Hematologic Malignancies Several CAR-T cell trials have shown high remission rates in patients with relapsed refractory hematologic cancers, including acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia and more recently multiple myeloma.1-6 More than 1000 patients have received CAR-T cells in the United States alone with more than 250 CAR-T cell trials listed in clinicaltrials.gov, primarily from the United States and China.7 Three major studies summarized in Table 1 have reported impressive complete remission (CR) rates of 81-89% with CAR-T cells targeting CD19 in young patients up to the age of 26 as well as adult patients2 with refractory ALL who have failed two or more prior regimens, with 40-50% of patients remaining in remission at one year.1,8 Table 2 summarizes three major studies in adults with refractory B cell lymphomas who had failed at least two prior regimens demonstrating encouraging CR rates of 40-58%, with 30-40% of patients remaining in remission at one year.3 In both the refractory ALL and NHL settings, the responses associated with these CAR-T cell therapies appeared to be significantly superior to what could be achieved with standard therapies, leading to the Food and Drug Administration (FDA) approval of Tisagenlecleucel (Kymriah) in August 2017 for patients with refractory ALL up to the age of 26, and for adults with refractory lymphoma in May 2018, with approval of Axicabtagene Ciloleucel (Yescarta) for adults with refractory lymphoma in October 2017.1,8,9 More recently, a phase I CAR-T cell trial was reported using an autologous CAR-T cell product targeting B-cell maturation antigen (BCMA) in patients with multiple myeloma who had failed at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or disease refractory to both drug classes.10 The objective response rate reported was 85% with 45% of patients experiencing a CR, demonstrating encouraging efficacy in these heavily pre-treated patients...There was no evidence of CAR T-cell related grade 3 or higher CRS or ICANS.22 The HEROS study, NCT00902044, is testing an anti-HER2 CAR-T cell in pediatric and adult patients with advanced refractory or metastatic heavily pretreated HER2-positive sarcomas.23 Ten patients were treated with up to three infusions of autologous HER2-targeted CAR-T cells after lymphodepletion with either fludarabine or fludarabine and cyclophosphamide...Cancer testis antigens are the most commonly used antigens (NY-ESO-1 being the most commonly targeted antigen).25 Toxicities It is important to note that severe toxicities with TCR-T cell therapy have been reported in the past, which are different from CRS or ICANS.29-31 In 2009, 3 patients treated with a TCR-T cell product targeting CEA developed severe inflammatory colitis, which lead to the termination of the trial.29 In 2011, 3 of 9 patients with solid tumors who received a MAGE-A3 TCR-T product developed severe neurotoxicity due to cross-reactivity against MAGE-A12, which is also expressed in normal brain.30 Another study with a MAGEA3 TCR resulted in the death of 2 patients due to cardiogenic shock within one week following the infusion...Conclusion In summary, taking the more mature results with cell therapy for hematologic cancers, and the more recent encouraging results in solid tumors, we believe the future for cellular therapy is bright. Continued refinements to reduce toxicity while enhancing the therapeutic benefit will be critical in the coming years, while reducing costs and making these therapies widely available for our cancer patients who need them.
- |||||||||| Actemra IV (tocilizumab) / Roche, JW Pharma
CAR-T Cells () - Sep 26, 2019 - Abstract #SOHO2019SOHO_281;
Both products are then usually administered following a short course of lymphodepleting chemotherapy, usually with fludarabine and cyclophosphamide...Following CAR-T cell infusion, patients are at risk for the complications of cytokine release syndrome (CRS) and neurologic toxicity (NT) which require management in the hospital setting.Data have now been reported from the primary clinical trials (Zuma-1 for axi-cel and Juliet for tisagenlecleucel) and both demonstrate encouraging rates of early complete remissions, with 30-40% durable remissions at 1-2 years of follow-up...This requires inpatient management and more frequent use of tocilizumab and steroids to control symptoms.A third CAR-T cell product, lisocabtagene maraleucel (liso-cel, JCAR-017) is in late stage clinical development in the same relapsed/refractory DLBCL setting...Despite the complexity of this approach, these treatments represent an exciting new treatment option. It is likely that the treatments will get more effective and less toxic in the future, further improving results for our patients.
- |||||||||| Rituxan (rituximab) / Roche, Biogen
Debate: Is Transplant Still Necessary in the Era of Targeted Cellular Therapy for ALL? CON () - Sep 26, 2019 - Abstract #SOHO2019SOHO_265;
At the same time, the addition of tyrosine kinase inhibitors (TKIs), CD20 antibodies such as rituximab, and intensive risk-directed therapy has led to continued improvements in up-front cure of patients with chemotherapy...In addition, tisagenlecleucel and other 4-1BB-based CAR T-cell approaches have induced remissions that in some cases are exceeding 6 years, showing that cures can occur without HCT in a high percentage of patients. Approaches aimed at optimizing CAR T-cell expansion and persistence along with targeting of multiple antigens are likely to lead to additional improvements in survival after CAR T-cells alone, further diminishing to role for HCT in this disease.
- |||||||||| Darzalex IV (daratumumab) / J&J
Childhood Acute Lymphoblastic Leukemia: How to Cure the Very High Risk? () - Sep 26, 2019 - Abstract #SOHO2019SOHO_242;
In a recent global study of 75 patients with relapsed or refractory B-ALL treated with tisagenlecleucel, the overall complete remission rate within 3 months was 81%, and the 12-month event-free and overall survival rates were 50% and 76%, respectively.31 Although these immunotherapy and adoptive cellular therapies have been used in the relapse or refractory setting, they are being brought forward to newly diagnosed B-ALL patients and promise to improve the outcome of these patients...Nonetheless, preclinical studies have shown efficacy with the anti-CD38 monoclonal antibody daratumumab and with CAR-T cells targeting several antigens, including CD2, CD5, and CD7 in T-ALL.32,33 In a recent Children’s Oncology Group trial AALL0434 for T-ALL, patients randomized to receive nelarabine have excellent treatment outcome.34 Since the vast majority of the patients received prophylactic cranial irradiation, additional studies are needed to determine if nelarabine can by itself improve CNS disease control.Conclusions Improved genomic sequencing and biologic understanding of ALL as well as integration of novel molecular, immunological and cellular therapy should continue to advance the cure rate for B-ALL. For T-ALL, better methods to identify patients at risk of relapse and more effective personalized therapies are needed.Funding Supported in part by National Cancer Institute grants CA21765, CA36401, CA176063 and P50 GM115279; and the American Lebanese and Syrian Associated Charities (ALSAC).
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis
Enrollment open, Phase classification: Phase III B in Acute Lymphoblastic Leukemia (clinicaltrials.gov) - Sep 23, 2019
P3, N=72, Recruiting,
For T-ALL, better methods to identify patients at risk of relapse and more effective personalized therapies are needed.Funding Supported in part by National Cancer Institute grants CA21765, CA36401, CA176063 and P50 GM115279; and the American Lebanese and Syrian Associated Charities (ALSAC). Available --> Recruiting | Phase classification: PN/A --> P3
- |||||||||| Lentiviral-based CART-meso gene therapy / University of Pennsylvania
Trial completion, Trial completion date, Trial primary completion date, Gene therapy: CART-meso Long-term Follow-up (clinicaltrials.gov) - Sep 19, 2019
P=N/A, N=10, Completed,
More research is needed to determine the optimal dose and schedule of tocilizumab for treatment of CAR T cell-induced CRS. Active, not recruiting --> Completed | Trial completion date: Mar 2030 --> Jul 2019 | Trial primary completion date: Mar 2030 --> Jul 2019
- |||||||||| birinapant (TL 32711) / Medivir, LMB-100 / National Cancer Institute, Roche
Synergy between IAP inhibitors and a cytotoxic antibody-based chimeric protein in pancreatic cancer cells (Board 18: Level 2 - Hall D) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_51;
The immunotoxin, LMB-100, targets surface mesothelin on pancreatic tumor cells but when tested on two pancreatic adenocarcinoma cell lines, AsPC1 and BxPc3, there was no detectable reduction in cell viability...BxPC3 cells remained resistant to the immunotoxin even in the presence of birinapant: the combination with the highest concentrations of both compounds reduced cell viability only to 50% after 72 hours... knowing the level of key proteins involved in the cell death pathway can explain the efficacy of drug combinations and could be used to predict responses.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Daiichi Sankyo
Use of luminescent xenograft and 3D In vitro tumor models in pharmacology studies of chimeric antigen receptor-T (CAR-T) cells (Board 16: Level 2 - Hall D) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_48;
In summary, utilizing xenograft models with luciferase-labeled cancer cell lines, we can investigate the efficacy of experimental CAR-T therapies to treat liquid and solid tumors. Additionally, the use of in vitro 3D-hTME culture shows promising results as a potential earlier-stage preclinical screen for the assessment of CAR T activity.
- |||||||||| autologous T cells expressing BCMA-specific chimeric antigen receptors (CART-BCMA) / University of Pennsylvania
Clinical, Journal: Allogeneic CAR-T for treatment of relapsed and/or refractory multiple myeloma: four cases report and literatures review (Pubmed Central) - Sep 16, 2019
They were infused into CART-19 (1×10(7)/kg on day 0) and (4.0-6.8) ×10(7)/kg CART-BCMA cells as split-dose infusions (40% on day 1 and 60% on day 2)...There were early clinical transient events after transfusion. Low amplification and short duration of CAR-T cells in vivo may be the main factors affecting the efficacy.
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