Kooperativer Bibliotheksverbund

In: Molecular Pharmaceutics, American Chemical Society (ACS), Vol. 12, No. 8 ( 2015-08-03), p. 2712-2731

Type of Medium: Online Resource

ISSN: 1543-8384 , 1543-8392

URL: Article

DOI: 10.1021/mp500646d

Language: English

Publisher: American Chemical Society (ACS)

Publication Date: 2015

detail.hit.zdb_id: 2132489-X

SSG: 15,3

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 3048-3048

Abstract: 3048 Background: Autologous chimeric antigen receptor (CAR) T therapies are highly efficient at targeting hematological malignancies, but the clinical applications have been limited by individualized manufacturing. Furthermore, there has been little success in treating solid tumors due to immunosuppressive microenvironments. Currently, genome editing technologies are being used to address both issues. However, the CRISPR/Cas9 system has significant safety concerns due to high incidence of off-target mutations and TALEN only works sufficiently in activated cells. A hybrid gene editing system, NextGEN (NG) Clo51-dCas9, can be targeted using gRNA, like CRISPR/Cas9, but exhibits little-to-no off-target cutting like TALEN, thereby overcoming limitations in the genome editing of resting T cells. Methods: We successfully developed a platform for production of allogeneic CAR-T cells with reduced receptivity to inhibitory signaling. Here, T cells were modified by piggyBac-mediated BCMA CAR gene delivery, along with NG reagents to knock out critical genes mediating rejection responses. Gene edited CAR-T cells were assessed by mixed lymphocyte reaction (MLR) and tumor killing. In addition, NG was used to knockout multiple checkpoint inhibitory receptors known to mediate key suppressive signals in T cells. Results: NG demonstrated high gene disruption efficiencies for all targets (84% for TCRα, 91% for TCRβ, 64% for β-2 microglobulin, and 40-60% for the surface inhibitory receptors PD-1, CTLA-4, Tim3, Lag-3, and TGFBRII). In contrast to CRISPR/Cas9, no off-target mutations were detected for multiple targets by deep-sequencing. In MLRs, disruption of TCR eliminated the GvHD response, while disruption of MHCI completely abrogated graft-rejection. Lastly, TCR/MHCI double knockout did not affect the ability to kill BCMA+ multiple myeloma cells in vitro. Conclusions: NG overcomes significant limitations of the CRISPR/Cas9 and TALEN systems with highly efficient genome editing in resting T cells. NG has great potential and flexibility for the manufacture of allogeneic CAR-T cells and for enhancing efficacy against solid tumors.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2017.35.15_suppl.3048

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2017

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4445-4445

Abstract: Chimeric Antigen Receptor (CAR) T cell therapy has generated unprecedented efficacy in the treatment of multiple hematologic malignancies. For relapsed/refractory Multiple Myeloma (MM), autologous CAR-T products directed against the B cell maturation antigen (BCMA), such as Poseida's P-BCMA-101, have demonstrated significant efficacy. P-BCMA-101 is comprised of a high-percentage of stem cell memory T cells (TSCM), resulting in a product that is much safer and potentially more durable than other anti-BCMA autologous product candidates. However, as individualized products, all autologous CAR-T products are expensive to manufacture and dependent upon patient T-cells of variable quality. We are developing P-BCMA-ALLO1, an off-the-shelf allogeneic (allo) BCMA-specific CAR-T product candidate derived from healthy donor material, which provides numerous advantages over autologous products, increasing patient access by being immediately available and greatly reducing manufacturing cost and variability. P-BCMA-ALLO1 is produced using two key platform technologies: the nonviral piggyBac® (PB) DNA Modification System and the high-fidelity Cas-CLOVER™ (CC) Site-Specific Gene Editing System. The mRNA coding for hyperactive, or "Super PB" transposase (SPB), and CC enzymes are codelivered with the P-BCMA-ALLO1 PB-based DNA transgene via electroporation to healthy donor T cells to stably integrate the transgene, as well as to knockout (KO) several mediators of allo graft-versus-host and host-versus-graft responses to maximize patient safety and durability of response. The P-BCMA-ALLO1 transgene encodes three genes, a BCMA-specific single-domain variable heavy chain (VH)-CAR (VCAR) gene, a drug selection gene to generate a ~100% CAR+ product, as well as a caspase-based safety switch gene to reduce or eliminate the product in vivo, if desired. The CC System is used to KO the endogenous T Cell Receptor (TCR) and beta-2 microglobulin, thereby decreasing Major Histocompatibility Complex (MHC) class I expression. KO of these key targets is aimed to prevent graft-versus-host disease, as well as reduce host-versus-graft rejection of the product. The CC System can efficiently edit resting T cells, thereby maintaining a high-percentage of TSCM cells, and does not create unwanted off-target mutations, another important consideration when creating an allo product candidate. To maximize the number of doses produced from a single manufacturing run, we have developed a proprietary "booster molecule" that allows for significant expansion of TCR-KO CAR-TSCM cells to potentially produce hundreds of doses. To date, large-scale manufacturing of significant doses of potent allo CAR-T products has been challenging for the field. P-BCMA-ALLO1 manufacturing uses a potentially unlimited number of individual serial donors. We have currently produced P-BCMA-ALLO1 at both research and near-commercial scale from 〉 35 donors with 〉 97% manufacturing success. While a range of TCR-KO efficiencies was observed (~50-90%), the final product was always 〉 99% homozygous TCR-KO after a purification step. Overall expansion of TCR-KO cells ranged from ~2-20 fold, and after removal of unedited TCR+ cells ~0.42-7.04x10e9 TCR-KO cells were recovered from 0.75x10e9 starting cells. However, working at clinical production scale (starting with ~3x10e9 cells), up to 250 doses of P-BCMA-ALLO1 could be manufactured per run, at a dose of 150x10e6 cells/patient. Importantly, with this level of donor and manufacturing robustness, no significant prior screening of donor material, other than to meet standard FDA requirements, would be needed. P-BCMA-ALLO1 made from multiple donors were comprised of an exceptionally high-percentage of the desirable TSCM cells (CD45RA+CD62L+CD45RO-) and had minimal to no expression of exhaustion markers, such as PD-1 or Lag3. Furthermore, P-BCMA-ALLO1 demonstrated potent efficacy in the RPMI-8226 xenograft model in NSG mice across multiple products generated from separate individual healthy donors. Altogether, these data demonstrate a robust, reproducible and highly scalable manufacturing process. Moreover, this manufacturing process can easily be expanded for use with additional CAR targets for treatment of other hematologic or solid tumor malignancies. Disclosures Cranert: Poseida Therapeutics: Employment, Equity Ownership. Richter:Poseida Therapeutics: Employment, Equity Ownership. Tong:Poseida Therapeutics: Employment, Equity Ownership. Weiss:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Tan:Poseida Therapeutics: Employment, Equity Ownership. Ostertag:Poseida Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Coronella:Poseida Therapeutics, Inc: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-131839

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2167-2167

Abstract: Immunotherapy using chimeric-antigen receptor (CAR)-T cells is emerging as an exciting therapeutic approach for cancer therapies. Autologous CAR-modified T cells targeting a tumor-associated antigen (Ag) can result in robust tumor killing, in some cases resulting in complete remission of CD19+ hematological malignancies. Unlike traditional biologics and chemotherapeutics, CAR-T cells possess the capacity to rapidly reproduce upon Ag recognition, thereby potentially obviating the need for repeat treatments. To achieve this, CAR-T cells must not only drive tumor destruction initially, but must also persist in the patient as a stable population of viable memory T cells to prevent potential cancer relapses. Thus, intensive efforts have been focused on the development of CAR molecules that do not cause T cell exhaustion through Ag-independent (tonic) signaling, as well as of a CAR-T product containing early memory cells, especially stem cell memory (TSCM). It is hypothesized that a stem cell-like CAR-T would exhibit the greatest capacity for self-renewal and multipotent capacity to derive central memory (TCM), effector memory (TEM) and effector T cells (TE), thereby producing better tumor eradication and long-term CAR-T engraftment. We developed a novel Centyrin-based CAR, referred to as a CARTyrin, that is specific for human B cell maturation antigen (BCMA). Centyrins are alternative scaffold molecules based on human consensus tenascin FN3 domain, are smaller than scFv molecules, and can be selected for monomeric properties that favor stability and decrease the likelihood of tonic signaling in CAR molecules. We produced a plasmid DNA transposon encoding the CARTyrin that was flanked by two cis-regulatory insulator elements to help stabilize CARTyrin expression by blocking improper gene activation or silencing. The piggyBac™ (PB) Transposon System was used for stable integration of anti-BCMA CARTyrin into resting pan T cells, whereby the transposon was co-delivered along with an mRNA transposase enzyme, called Super piggyBac™ (SPB), in a single electroporation reaction. Delivery of piggyBac™ transposon into untouched, resting primary human pan T cells resulted in 20-30% of cells with stable integration and expression of PB-delivered genes. Surprisingly, we observed that a majority of these cells were positive for expression of CD62L and CD45RA, markers commonly associated with TSCM cells. To see if this phenotype was retained upon CAR-T cell stimulation and expansion, we activated the cells via stimulation of CD3 and CD28, and later show that 〉 60% of CARTyrin+ T cells exhibited a stem-cell memory phenotype. Furthermore, these cells were fully capable of expressing potent anti-tumor effector function. To determine whether or not the PB system directly contributed to enhancing the expression of stem-like markers, we compared the phenotype of CAR-T cells generated either by PB transposition or lentiviral (LV) transduction. To do this, we constructed a new vector by subcloning the CARTyrin transgene into a common LV construct for production of virus. Following introduction of the CARTyrin to untouched resting T cells either by PB-transposition or LV-transduction, we expanded the CARTyrin+ cells and then allowed them to return to a resting state. A variety of phenotypic and functional characteristics were measured including kinetic analysis of memory and exhaustion-associated markers, secondary proliferation in response to homeostatic cytokine or tumor-associated Ag, cytokine production, and lytic capability in response to BCMA+ tumor cells. Unlike the PB-transposed CARTyrin+ T cells, we found that the LV-transduced CARTyrin+ T cells did not exhibit an augmented memory phenotype. In addition, PB-transposed cells exhibited a comparable or greater capability for secondary proliferation and killing of BCMA+ tumor cells. Together, these data demonstrate that CAR-T cells produced by PB transposition are predominantly TSCM cells, a highly desirable product phenotype in the CAR-T field. Furthermore, these CARTyrin+ T cells exhibit strong anti-tumor activity and may give rise to cells that persist longer in vivo due to the use of a Centyrin-based CAR, which may be less prone to tonic signaling and functional exhaustion. Disclosures Barnett: Poseida Therapeutics: Employment. Hermanson:Poseida Therapeutics: Employment. Smith:Poseida Therapeutics: Employment. Wang:Poseida Therapeutics: Employment. Tan:Poseida Therapeutics: Employment. Martin:Poseida Therapeutics: Employment. Osertag:Poseida Therapeutics: Employment, Equity Ownership. Shedlock:Poseida Therapeutics: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.2167.2167

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2127-2127

Abstract: Chimeric-antigen receptor (CAR)-T cell immunotherapies have been remarkably effective in treating acute lymphoblastic leukemia. However, current strategies generally suffer from difficult, inefficient and costly manufacturing processes, significant patient side effects and poor durability of response in some patients. Here, we report for the first time a CAR-T cell therapeutic comprising a non-immunoglobulin alternative scaffold Centyrin molecule (a "CARTyrin") manufactured with a novel non-viral piggyBacTM (PB) transposon-based system. Our lead candidate, P-BCMA-101, encodes a CARTyrin that targets the B cell maturation antigen (BCMA) for the treatment of multiple myeloma (MM) and has several unique aspects that improve upon earlier CAR-T products. First, P-BCMA-101 is manufactured using only in vitro transcribed mRNA and plasmid DNA without the need for lentivirus or g-retrovirus, resulting in time and cost savings. Importantly, PB is also safer than viral systems due to a less mutagenic insertional profile and is non-oncogenic. Furthermore, PB can efficiently deliver transgenes as large as several hundred kilobases, and, once inserted, transgenes demonstrate more stable, prolonged and higher expression when compared to those delivered by virus. Second, a mutein of the dihydrofolate reductase (DHFR) gene is included in the P-BCMA-101 transgene that can be used in combination with the non-genotoxic drug methotrexate (MTX) to provide a simple and effective method of CARTyrin+ cell enrichment and reduces variability in patient product material. Third, P-BCMA-101 incorporates a safety switch for optional depletion in vivo in case of adverse events. Lastly, the CARTyrin is comprised of a BCMA-specific Centyrin, which are based on a human tenascin fibronectin type III (FN3) consensus sequence. Centyrins have similar binding affinities to the antibody-derived single chain variable fragments (scFv), but are smaller, more thermostable and predicted to be less immunogenic. Importantly, no signs of tonic signaling leading to T cell exhaustion have been observed with CARTyrins unlike scFv-based CAR molecules, which can interact with each other on the surface causing non-specific CAR signaling. The manufacture process of P-BCMA-101 from primary human T cells is straightforward, employs no cytokines, and easily produces enough CARTyrin+ cells to treat patients. Within 18 days of electroporation of purified T cells, we demonstrate 〉 95% of the cell product is positive for CARTyrin expression and ready to be administered. Notably, our manufacturing process results in 〉 60% of CARTyrin+ T cells exhibiting a stem-cell memory phenotype (i.e. CD45RA+ CD62L+). P-BCMA-101 cells exhibit specific and robust in vitro activity against BCMA+ tumor targets, ranging from high to very low levels of BCMA, as measured by target-cell killing and CARTyrin-T cell proliferation. Importantly, proliferating P-BCMA-101 cells were highly sensitive in vitro to activation of the safety switch. Finally, we have evaluated the anti-tumor efficacy of P-BCMA-101 in a model of human MM. NSG™ mice were injected IV with 1.5x106 luciferase+ MM.1S cells, an aggressive human MM-derived cell line. After the tumor cells were allowed to grow for 21 days, animals received a single IV administration of 5x106 P-BCMA-101 cells. All untreated control animals demonstrated a marked increase in serum M-protein levels, rapid growth of tumor cells demonstrated by bioluminescent imaging (BLI), and death within four weeks. In stark contrast, 100% of animals that received P-BCMA-101 rapidly eliminated tumors within 7 days as measured by BLI and serum M-protein levels and improved survival out to at least 60 days post-treatment. P-BCMA-101 is the first-in-class of Centyrin-based CAR therapeutics. The CARTyrin, combined with our advanced manufacturing processes, represents a significant improvement over first generation, immunoglobulin-based and virally-transduced CAR-T products. P-BCMA-101 exhibited an advantageous stem-cell memory phenotype and demonstrated specific and potent anti-tumor efficacy against BCMA+ myeloma cells both in vitro and in vivo. Based on these results, we plan to initiate a phase I clinical trial of P-BCMA-101 for the treatment of patients with relapsed and/or refractory MM. Disclosures Hermanson: Poseida Therapeutics: Employment. Barnett:Poseida Therapeutics: Employment. Rengarajan:Poseida Therapeutics: Employment. Codde:Poseida Therapeutics: Employment. Wang:Poseida Therapeutics: Employment. Tan:Poseida Therapeutics: Employment. Martin:Poseida Therapeutics: Employment. Smith:Poseida Therapeutics: Employment. Osertag:Poseida Therapeutics: Employment, Equity Ownership. Shedlock:Poseida Therapeutics: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.2127.2127

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT130-CT130

Abstract: Background: P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell therapy designed to increase efficacy while minimizing toxicity through reduced immunogenicity, lack of tonic signaling, a safety switch, high purity ( & gt95% CAR+) and a Tscm phenotype (Tscm are long-lived lymphocyte stem cells that appear to gradually differentiate into effectors, improving efficacy, durability and safety of a CAR-T therapeutic). The P-BCMA-101 CAR utilizes an anti-BCMA (B-Cell Maturation Antigen) Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than antibody fragments. Centyrins are fully human and have high binding affinities, but are smaller, more stable and potentially less immunogenic. This product is made using the piggyBac™ (PB) transposon system, requiring only mRNA and plasmid DNA. PB eliminates the need for virus, preferentially producing the desired Tscm phenotype and reducing manufacturing costs. The higher cargo capacity of PB also permits the incorporation of other genes, such as a safety switch and a selection gene in P-BCMA-101. The former allows for in vivo depletion of P-BCMA-101 if severe adverse events were to occur and the latter allows enrichment of CAR+ cells leading to greater consistency and purity to produce a better therapeutic index. Efficacy of P-BCMA-101 in NSG mice bearing aggressive human MM.1S and p53 -/- MM.1S MM was reported (Hermanson, AACR 2016). Whereas control animals died early, tumor burden was reduced to the limit of detection after P-BCMA-101 treatment, and recurrences were spontaneously re-controlled. Objectives & Methodology: Thus, a 3+3 dose escalation Phase 1 clinical trial was initiated in patients with r/r MM to assess the safety and efficacy of P-BCMA-101 (NCT03288493). Patients are apheresed to harvest T cells, then P-BCMA-101 CARTyrin T cells are manufactured and administered to patients as a single dose after a standard cyclophosphamide/fludarabine conditioning regimen. Preliminary Results: Two heavily pretreated patients are thus far evaluable at a dose of 0.75 x 106 CARTyrin+ cells / kg. P-BCMA-101 manufactured for patients were primarily Tscm, and demonstrated robust and specific in vitro killing and cytokine production against BCMA+ tumor cells. Both patients' MM was BCMA+. Patient 1, a 54yo female with λ light chain myeloma had rapid progression in spite of chemotherapy, with free light chains (FLC) spiking to 3290 mg/L and renal failure prior to P-BCMA-101 treatement. After P-BCMA-101 administration a partial response was reported, with FLC rapidly decreasing from 1308 mg/L at baseline to 305 mg/L. No cytokine release syndrome (CRS) was seen, though there were mild elevations in CRS markers. Patient 2 is a 50yo female with oligosecretory κ light chain myeloma with plasmacytomas. Likewise, no CRS was reported. PET/CT is pending. P-BCMA-101 CARTyrin T cells markedly expanded and persisted in both patients, comprising 14-40% of circulating T cells within 3 weeks of infusion. Both patients continue in good condition, and additional patients have been enrolled. Clinical trial data are early, but appear consistent with the preclinical findings for P-BCMA-101. Funding for this study was provided by Poseida Therapeutics and CIRM Citation Format: Tara K. Gregory, Jesus G. Berdeja, Krina K. Patel, Syed Abbas Ali, Adam D. Cohen, Caitlin Costello, Eric M. Ostertag, Nishan de Silva, Devon J. Shedlock, Michelle Resler, Matthew A. Spear, Robert Z. Orlowski. Clinical trial of P-BCMA-101 T stem cell memory (Tscm) CAR-T cells in relapsed/refractory (r/r) multiple myeloma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT130.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2018-CT130

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2018

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3184-3184

Abstract: P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell product targeting B Cell Maturation Antigen (BCMA). P-BCMA-101 is produced using the piggyBac® (PB) DNA Modification System instead of the viral vector that is used with most CAR-T cells, requiring only plasmid DNA and mRNA. This makes it less costly and produces cells with a high percentage of the favorable T stem cell memory phenotype (TSCM). The higher cargo capacity of PB permits the incorporation of multiple genes in addition to CAR(s), including a safety switch allowing for rapid CAR-T cell elimination with a small molecule drug infusion in patients if desired, and a selection gene allowing for enrichment of CAR+ cells. Rather than using a traditional antibody-based binder, P-BCMA-101 has a Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human proteins with high specificity and a large range of binding affinities, but are smaller, more stable and potentially less immunogenic than traditional scFv. Cumulatively, these features are predicted to result in a greater therapeutic index. A Phase 1, 3+3 dose escalation from 0.75 to 15 x 106 P-BCMA-101 CAR-T cells/kg (RP2D 6-15 x 106 cells/kg) was conducted in patients with r/r MM (Blood 2018 132:1012) demonstrating excellent efficacy and safety of P-BCMA-101, including notably low rates and grades of CRS and neurotoxicity (maximum Grade 2 without necessitating ICU admission, safety switch activation or other aggressive measures). These results supported FDA RMAT designation and initiation of a pivotal Phase 2 study. A Phase 2 pivotal portion of this study has recently been designed and initiated (PRIME; NCT03288493) in r/r MM patients who have received at least 3 prior lines of therapy. Their therapy must have contained a proteasome inhibitor, an IMiD, and CD38 targeted therapy with at least 2 of the prior lines in the form of triplet combinations. They must also have undergone ≥2 cycles of each line unless PD was the best response, refractory to the most recent line of therapy, and undergone autologous stem cell transplant or not be a candidate. Patients are required to be 〉 =18 years old, have measurable disease by International Myeloma Working Group criteria (IMWG; Kumar 2016), adequate vital organ function and lack significant autoimmune, CNS and infectious diseases. No pre-specified level of BCMA expression is required, as this has not been demonstrated to correlate with clinical outcomes for P-BCMA-101 and other BCMA-targeted CAR-T products. Interestingly, unlike most CAR-T products patients may receive P-BCMA-101 after prior CAR-T cells or BCMA targeted agents, and may be multiply infused with P-BCMA-101. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose (6-15 x 106 P-BCMA-101 CAR-T cells/kg) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. One hundred patients are planned to be treated with P-BCMA-101. Uniquely, given the safety profile demonstrated during Phase 1, no hospital admission is required and patients may be administered P-BCMA-101 in an outpatient setting. The primary endpoints are safety and response rate by IMWG criteria. With a 100-subject sample, the Phase 2 part of the trial will have 90% power to detect a 15-percentage point improvement over a 30% response rate (based on that of the recently approved anti-CD38 antibody daratumumab), using an exact test for a binomial proportion with a 1-sided 0.05 significance level. Multiple biomarkers are being assessed including BCMA and cytokine levels, CAR-T cell kinetics, immunogenicity, T cell receptor diversity, CAR-T cell and patient gene expression (e.g. Nanostring) and others. Overall, the PRIME study is the first pivotal study of the unique P-BCMA-101 CAR-T product, and utilizes a number of novel design features. Studies are being initiated in combination with approved therapeutics and earlier lines of therapy with the intent of conducting Phase 3 trials. Funding by Poseida Therapeutics and the California Institute for Regenerative Medicine (CIRM). Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Ali:Celgene: Research Funding; Poseida: Research Funding. Berdeja:Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding. Patel:Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding; Poseida Therapeutics, Cellectis, Abbvie: Research Funding. Shah:University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Ghoddusi:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129562

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: The Journal of Infectious Diseases, Oxford University Press (OUP), Vol. 219, No. 4 ( 2019-01-29), p. 544-555

Abstract: There remains an important need for prophylactic anti-Ebola virus vaccine candidates that elicit long-lasting immune responses and can be delivered to vulnerable populations that are unable to receive live-attenuated or viral vector vaccines. Methods We designed novel synthetic anti-Ebola virus glycoprotein (EBOV-GP) DNA vaccines as a strategy to expand protective breadth against diverse EBOV strains and evaluated the impact of vaccine dosing and route of administration on protection against lethal EBOV-Makona challenge in cynomolgus macaques. Long-term immunogenicity was monitored in nonhuman primates for & gt;1 year, followed by a 12-month boost. Results Multiple-injection regimens of the EBOV-GP DNA vaccine, delivered by intramuscular administration followed by electroporation, were 100% protective against lethal EBOV-Makona challenge. Impressively, 2 injections of a simple, more tolerable, and dose-sparing intradermal administration followed by electroporation generated strong immunogenicity and was 100% protective against lethal challenge. In parallel, we observed that EBOV-GP DNA vaccination induced long-term immune responses in macaques that were detectable for at least 1 year after final vaccination and generated a strong recall response after the final boost. Conclusions These data support that this simple intradermal-administered, serology-independent approach is likely important for additional study towards the goal of induction of anti-EBOV immunity in multiple at-risk populations.

Type of Medium: Online Resource

ISSN: 0022-1899 , 1537-6613

URL: Article

DOI: 10.1093/infdis/jiy537

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2019

detail.hit.zdb_id: 1473843-0

In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 225.8-225.8

Abstract: The 2013–2016 Ebola virus disease (EVD) was the first time that the spread of the virus reached epidemic status. There are no licensed vaccines; however the most advanced candidate rVSV-ZEBOV vaccine, is a live-attenuated vesicular stomatitis virus encoding the Ebola virus glycoprotein (GP), and has demonstrated efficacy in a ring-vaccination trial. However, several EVD viral vector vaccine trials have reported adverse events that could limit administration to certain populations. The establishment of robust anamnestic responses has yet to be fully understood with these candidates and may be limited by potential anti-vector immunity. We designed EVD DNA vaccines as an alternative platform with a remarkable safety profile that is serology independent, allowing for possible repeat vector administration. We designed 3 novel synthetic Zaire Ebola virus (EBOV) GP DNA sequences which were tested alone or as multivalent formulations delivered by in vivo intramuscular (IM) or intradermal (ID) electroporation (EP). The EBOV-GP DNA vaccines were highly protective against lethal EBOV-Makona challenge in cynomolgus macaques, with 100% protection in NHPs receiving vaccine by ID-EP delivery and 75% protection in NHPs receiving 2 doses IM-EP. Vaccinated NHPs had no detectable viremia following challenge. Animals (n=4–5/group) injected with different IM-EP or ID-EP DNA regimens were followed to monitor long-term immunogenicity. NHPs have durable total IgG antibody titers and T cells responses to EBOV GP antigen, including polyfunctional CD4 and CD8 T cells and responses in memory subset populations. Together, the data strong support EBOV-GP DNA vaccine delivery for protection and the generation of robust memory immune responses.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.198.Supp.225.8

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2017

detail.hit.zdb_id: 1475085-5

In: Vaccine, Elsevier BV, Vol. 33, No. 35 ( 2015-08), p. 4313-4320

Type of Medium: Online Resource

ISSN: 0264-410X

URL: Article

DOI: 10.1016/j.vaccine.2015.03.086

Language: English

Publisher: Elsevier BV

Publication Date: 2015

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