Kooperativer Bibliotheksverbund

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 16_Supplement ( 2018-08-15), p. A071-A071

Kurzfassung: Prostate-specific membrane antigen isoform 1 (PSMA) is a transmembrane glycoprotein overexpressed in & gt;80% of primary and metastatic prostate cancers. PSMA is involved in folate uptake and confers a proliferative advantage to PSMA-expressing cells. Additionally, PSMA levels increase as cells become androgen-independent, a hallmark of advancing prostate disease. Although PSMA peptide and antibody drug conjugate therapies have shown promise, early first-generation chimeric antigen receptor (CAR) T-cell therapies have lacked clinical efficacy. Here we developed a novel CAR T-cell product (P-PSMA-101) via piggyBac™ transposition of a tri-cistronic transgene encoding a safety switch, a PSMA-specific Centyrin-based CAR (CARTyrin), and a selection gene—features that may improve safety and efficacy compared with previous anti-PSMA CAR T-cell therapies. We first developed and identified a lead anti-PSMA CARTyrin from over 250 available Centryin binders. We also tested the previously clinically applied anti-PSMA J591 scFv-based CAR for comparability. Initial assessment utilized mRNA delivery of candidate CARTyrins to confirm CAR surface expression and specific T-cell degranulation against PSMA+ prostate tumor cells or PSMA-engineered cells. We then used piggyBac to deliver our tri-cistronic vector system encoding the lead PSMA CARTyrin (P-PSMA-101), J591 scFv CAR, or a BCMA-specific CARTyrin to T cells, resulting in & gt;95% CAR+ T cells after selection and expansion. Importantly, our unique production methodology leads to & gt;60% T-stem cell memory (Tscm) cells, an early memory population that correlates with complete responses in CD19 CAR T-cell clinical trials. In vitro, P-PSMA-101 and J591 CAR T cells specifically proliferated, lysed, and secreted IFN-γ against PSMA+ LNCaP or PSMA-engineered K562s. No evidence of tonic signaling or exhaustion was detected. P-PSMA-101 demonstrated significantly enhanced antitumor efficacy and survival in comparison to J591 CAR T cell-treated mice (P-PSMA-101 & gt;110 days versus J591 41 days) in a low “stress test” dose of T cells against established subcutaneous LNCaP(fLuc+) solid tumors in NSG mice. The & gt;60% Tscm P-PSMA-101 expanded in vivo and gave rise to differentiated effector CAR+ T cells that were detected in the peripheral blood concomitant with a decrease in tumor burden below detectable caliper and bioluminescent imaging limits. P-PSMA-101 then contracted, yet persisted in the peripheral blood with & gt;70% of T cells exhibiting a Tscm phenotype. On the contrary, J591 CAR T cells did not significantly control tumor burden or expand to appreciable levels in the peripheral blood. In a dose titration study, P-PSMA-101 eliminated established LNCaP tumor in 100% of animals for the duration of the studies (42 days post-treatment), while 2/3 low-dose animals remained tumor-free. Ongoing in vivo studies point towards potent antitumor effects in aggressive bone metastases models of prostate cancer. P-PSMA-101 is a first-in-class Centyrin-based CAR T-cell therapeutic that exhibits a persistently high frequency of Tscm and mediates durable anti-solid tumor efficacy that surpasses previously established anti-PSMA CAR T-cell therapy in our in vivo models. Future efforts will continue towards clinical application of P-PSMA-101 in patients with metastatic castrate-resistant prostate cancer. Citation Format: Jenessa Barbara Smith, Rebecca Codde, Yening Tan, Barnett E. Barnett, David Hermanson, Srinivas Rengarajan, Eric M. Ostertag, Devon J. Shedlock. PSMA-specific CARTyrin T-stem cell memory therapy eliminates solid tumor in subcutaneous prostate cancer model [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A071.

Materialart: Online-Ressource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.PRCA2017-A071

Sprache: Englisch

Verlag: American Association for Cancer Research (AACR)

Publikationsdatum: 2018

ZDB Id: 2036785-5

ZDB Id: 1432-1

ZDB Id: 410466-3

In: Molecular Therapy - Nucleic Acids, Elsevier BV, Vol. 29 ( 2022-09), p. 329-

Materialart: Online-Ressource

ISSN: 2162-2531

URL: Article

DOI: 10.1016/j.omtn.2022.07.021

Sprache: Englisch

Verlag: Elsevier BV

Publikationsdatum: 2022

ZDB Id: 2662631-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4802-4802

Kurzfassung: The emergence of CAR-T cell therapy has transformed the treatment of the previously refractory/relapsed multiple myeloma (MM). Yet, autologous CAR-T cells suffer from inconsistent manufacturing, long manufacturing timelines, and high cost, which can limit patient accessibility. To address these issues, we engineered a fully allogeneic anti-BCMA CAR-T cell candidate for MM from healthy donors (P-BCMA-ALLO1). Herein, we demonstrate that P-BCMA-ALLO1 maintains a T stem cell memory phenotype (T SCM) through genetic editing, which correlates with antitumor efficacy. Using Poseida's proprietary non-viral piggyBac® (PB) DNA Delivery System, in combination with the high-fidelity Cas-CLOVER™ (CC) Site-Specific Gene Editing System and a proprietary "booster molecule", we generated P-BCMA-ALLO1 from healthy donor T cells. We used CC to eliminate surface expression of TCR and MHC class I to make fully allogeneic CAR-T cells. In addition to the CAR molecule, PB enables the delivery of a selectable marker allowing the generation of a final cell product that is & gt;95% CAR-positive. The inclusion of the "booster molecule" in the manufacturing process improves the expansion of gene-edited cells without compromising memory phenotype or function. This process can produce up to hundreds of patient doses from a single manufacturing run using one healthy donor, thereby significantly reducing manufacturing cost per dose. We characterized the phenotype and functionality of P-BCMA-ALLO1 using flow cytometry and Nanostring to assess their memory phenotype at both the protein and mRNA levels. Also analyzed was antitumor toxicity and proliferative capacity through multiple rounds of activation using in vitro co-culture assays and serial restimulation, respectively. The relationship of all characterizations with in vivo efficacy was then determined, as defined by control of tumor growth in an immunodeficient RPMI-8226 subcutaneous murine tumor model. We found that P-BCMA-ALLO1 is comprised of a high frequency of T SCM after editing (Fig. 1), and the maintenance of that memory phenotype correlates with antitumor efficacy. In vivo, these CAR-T cells are potent in controlling tumor growth, comparable to or better than autologous anti-BCMA CAR-T cells. Our analysis revealed that the expression of memory markers at the surface protein level (CD27, CD62L, CD127, CCR7) and mRNA level significantly correlate with in vivo tumor control. Conversely, suboptimal research products with worse in vivo outcomes express a more exhausted gene expression profile. We reveal from our analysis that the most effective P-BCMA-ALLO1 in vivo share similar characteristics: (1) these products were a result of efficient manufacturing, with & gt;90% CAR+ and & gt;99% TCR-; (2) they carry a memory phenotype, with 50-70% T scm and high proliferative capacity after multiple rounds of restimulation; (3) they are & gt;90% viable; and (4) they show strong antitumor efficacy both in vitro and in vivo. We demonstrate that Tscm percentage in the final product correlates with antitumor activity. P-BCMA-ALLO1 is advancing rapidly towards the clinic (NCT04960579) to positively impact the outcomes of CAR-T therapy for MM patients. Figure 1: Memory composition of P-BCMA-ALLO1 research products. P-BCMA-ALLO1 consists mostly of stem cell memory (T scm) and central memory (T cm) T cells that are CD62L + as opposed to effector memory (T em) and effector (T eff) T cells. Figure 1 Figure 1. Disclosures Tseng: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhang: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cranert: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Richter: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Marquez: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Qiu: Poseida Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Cho: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tong: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Domingo: Poseida Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Weiss: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Argus: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sparks: Poseida Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Ostertag: Poseida: Current Employment, Current equity holder in publicly-traded company. Coronella: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shedlock: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-154034

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2021

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 98-98

Kurzfassung: 98 Background: P-PSMA-101 is an autologous CAR-T therapy targeting PSMA, with a high percentage of stem cell memory T cells (T SCM ) associated with efficacy, safety, and bone homing (particularly relevant to prostate cancer). It is manufactured using a novel non-viral transposon system (piggyBac) that creates high T SCM products. Genes are inserted encoding a PSMA-targeted Centyrin CAR, iCasp9-based safety switch, and DHFR to purify CAR-T cells. P-PSMA-101 completely eliminated tumors in intractable murine models of prostate cancer, providing rationale for this phase 1 trial (NCT04249947). Methods: Patients with mCRPC treated with or not eligible for a CYP17 inhibitor or second-generation antiandrogen, and a taxane were enrolled. P-PSMA-101 was manufactured from apheresed T cells and administered IV following a standard 3-day cy/flu lymphodepletion regimen. Dose escalation from 0.25-15 x 10 6 cells/kg is planned. Results: As of September 30, 2021, P-PSMA-101 had been administered to 10 heavily pretreated patients (median 7 prior regimens; range 3-15). Single infusions of 0.25 (n=5) to 0.75 (n=5) x 10 6 cells/kg have been assessed, with dose escalation continuing. P-PSMA-101 cells were shown to expand in blood via qPCR assay, peaking 2-3 weeks after infusion, consistent with the high percentage of T SCM . Significant antitumor responses were seen in this preliminary data set. Declines in PSA were seen in 7 patients ( 〉 50% in 3 and 〉 99% in 1). Of 4 patients who had pre- and post-treatment FDG and PSMA-PET imaging, 3 demonstrated marked to complete resolution of abnormal uptake at known metastatic disease sites, with concordance in bone and CT scans, and/or circulating tumor cells (CTC). In 1 case, post-treatment tumor biopsy demonstrated infiltration by P-PSMA-101 CAR-T cells and elimination of tumor cells (pathologic complete response). Safety was consistent with expectations for a CAR-T product. CRS was seen in 60% (10% Gr ≥3) of patients. DLT was seen in 1 patient with macrophage activation syndrome/uveitis, and was the only Gr ≥3 CRS event. Immune effector cell-associated neurotoxicity syndrome (ICANS) has not occurred. CRS marker elevations were modest (max IL-6: 642.6 pg/mL). The most common AEs were cytopenias, infections, and constitutional symptoms (Gr ≥3 60%, 10%, and 0%), as expected with lymphodepletion. Treatable related ocular AEs were noted in 3 patients. Conclusions: These results parallel preclinical findings that P-PSMA-101 can produce marked efficacy in mCRPC, and very low doses are highly efficacious, consistent with unique product attributes such as the T SCM phenotype and bone tropism. This is the first report demonstrating profound antitumor effects of a novel PSMA-directed CAR-T-cell platform with concordant biochemical, radiographic, and pathologic parameters, demonstrating that therapeutic benefit of unarmored CAR-T cells in a major solid tumor is possible. Clinical trial information: NCT04249947.

Materialart: Online-Ressource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2022.40.6_suppl.098

Sprache: Englisch

Verlag: American Society of Clinical Oncology (ASCO)

Publikationsdatum: 2022

ZDB Id: 2005181-5

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

Kurzfassung: 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.

Materialart: Online-Ressource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2017.35.15_suppl.3048

Sprache: Englisch

Verlag: American Society of Clinical Oncology (ASCO)

Publikationsdatum: 2017

ZDB Id: 2005181-5

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

Kurzfassung: 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.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-131839

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2019

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 29-30

Kurzfassung: P-BCMA-101 is an autologous chimeric antigen receptor-T cell (CAR-T) therapeutic targeting BCMA and comprised of a high percentage of desirable stem cell memory T cells. P-BCMA-101 is manufactured using a novel transposon-based system called piggyBac and is designed to increase efficacy while minimizing toxicity. A phase 1/2, clinical trial is being conducted in patients with r/r MM (≥ 3 prior lines, including a proteasome inhibitor and an IMiD, or double refractory) to assess the safety and efficacy of P-BCMA-101 (NCT03288493). No pre-specified level of BCMA expression was required. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients intravenously (IV) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) lymphodepletion regimen. As of 30Jun20, 43 patients had been treated with P-BCMA-101 (M/F 67%/33%, median age 60 years). Patients were heavily pre-treated (median of 7 prior regimens; range 3-18), with 100% having received proteasome inhibitors and IMiD, 93% daratumumab and 58% ASCT. This study was initially conducted as a dose escalation trial of single infusions of P-BCMA-101 from 0.75-15 x 106 cells/kg, preceded by standard lymphodepletion. Subsequently, exploratory cohorts with novel therapeutic strategies were evaluated. Using a modified manufacturing process, a median dose of 0.75 x 106 cells/kg were administered in cohorts including: P-BCMA-101 infusions in biweekly cycles; the addition of rituximab or lenalidomide pre- and post- lymphodepletion to prevent anti-CAR antibody development and increase T cell robustness, respectively; and single administration. The safety profile across the entire group was excellent for a CAR-T cell product which was attributed the gradual expansion of the Tscm cells (2-3 weeks to peak versus 3-7 days for most CAR-T cells). Cytokine release syndrome (CRS) was only seen in 17% of patients, with only one being grade 3 and one case of possible neurotoxicity reported (transient increase in confusion). Likewise, peak elevations of CRS markers were modest (maximum IL-6 level reported in any patient was 1631 pg/mL, orders of magnitude lower than levels frequently associated with severe CRS with CAR-T products). Only 3 patients required tocilizumab and no patients required ICU admission, safety switch activation or other aggressive measures. Based on the safety results the protocol was amended to allow fully outpatient CAR-T cell administration. There have been no patient deaths, DLTs or unexpected/off-target toxicities related to P-BCMA-101. The most common adverse events otherwise were cytopenias/infections and constitutional symptoms (≥ grade 3 neutropenia 79%, thrombocytopenia 30%, anemia 30%), as expected in CAR-T cell studies with lymphodepleting chemotherapy. Consistent with the high percentage of Tscm, circulating P-BCMA-101 cells were detected in blood by PCR, peaking at 2-3 weeks after infusion, and remaining detectable up to 1.5 years (ongoing at last follow-up). Response was seen to correlate with the Cmax and AUC of cell expansion, none of which correlated with dose administered. The overall response rate (ORR) for evaluable subjects (n=34) treated with single administration during the initial dose escalation was 57%. As there was not a definite dose response curve, but indications of better response at lower doses, additional cohorts were implemented focusing on the lower end of the dose range using product from the modified manufacturing process. Four patients were subsequently treated with cyclic administration, rituximab, lenalidomide or single administration at the lowest dose level with this manufacturing process (all treated with P-BCMA-101 within ~2 months prior to the data cut-off date), and thus far all have rapidly responded (100% ORR) and all responses are ongoing. The safety profile in these patients (including multiply infused patients) was no different than the overall population, with minimal CRS reported. In conclusion, current clinical data are consistent with preclinical findings that the novel design of P-BCMA-101 can produce significant efficacy, with remarkably low toxicity allowing for outpatient administration. Low doses appear highly efficacious and the modifications to manufacturing appear to have notably improved efficacy. Disclosures Costello: Poseida Therapeutics: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Cohen:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Patel:Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectis: Research Funding. Berdeja:Lilly: Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Bioclinica: Consultancy; Glenmark: Research Funding; Acetylon: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Legend: Consultancy; Bluebird: Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Teva: Research Funding; Servier: Consultancy; Amgen: Consultancy, Research Funding; Cellularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Prothena: Consultancy; Kite Pharma: Consultancy; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Constellation: Research Funding. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Ganguly:Kadmon: Other: Ad Board; KITE Pharma: Speakers Bureau; Settle Genetics: Speakers Bureau. Abedi:BMS, Gilead Sciences: Research Funding; AbbVie, BMS, Gilead Sciences, Seattle Genetics, Takeda: Speakers Bureau. Yalamanchili:Poseida Therapeutics: Current Employment, Current equity holder in private company. Gregory:Kesios: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Celularity: Research Funding; Teva: Research Funding; Vivolux: Research Funding; Lilly: Research Funding; Constellation: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Poseida: Research Funding; CRISP Therapeutics: Research Funding; CURIS: Research Funding; Acetylon: Research Funding; Incyte Corporation: Consultancy; Bluebird: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; EMD Sorono: Research Funding.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-142695

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2020

ZDB Id: 1468538-3

ZDB Id: 80069-7

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

Kurzfassung: 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.

Materialart: Online-Ressource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2018-CT130

Sprache: Englisch

Verlag: American Association for Cancer Research (AACR)

Publikationsdatum: 2018

ZDB Id: 2036785-5

ZDB Id: 1432-1

ZDB Id: 410466-3

In: Molecular Therapy - Nucleic Acids, Elsevier BV, Vol. 29 ( 2022-09), p. 979-995

Materialart: Online-Ressource

ISSN: 2162-2531

URL: Article

DOI: 10.1016/j.omtn.2022.06.003

Sprache: Englisch

Verlag: Elsevier BV

Publikationsdatum: 2022

ZDB Id: 2662631-7

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3759-3759

Kurzfassung: Chimeric antigen receptor (CAR) T cells have been extremely effective in treating acute lymphoblastic leukemia and have shown promise against other malignancies including multiple myeloma (MM). However, relatively poor potency and durability continue to limit efficacy. Addressing these shortcomings, we have developed a novel CAR-T cell therapeutic with enhanced stem cell memory phenotype, reduced immunogenicity, and no evidence of tonic activity. P-BCMA-101 employs a BCMA-specific Centyrin rather than a single chain variable fragment (scFv) for antigen detection and is engineered using piggyBac (PB). Centyrins are fully human and have similar binding affinities but are smaller, more thermostable and predicted to be less immunogenic than a scFv. Furthermore, PB modification of human T cells requires only in vitro transcribed mRNA and plasmid DNA, eliminating the need for lentivirus or γ–retrovirus and resulting in time and cost savings. Additionally, the increased cargo capacity of PB permits the incorporation of a safety switch and a selectable gene into the product. The former is incorporated for optional depletion in vivo in case of adverse events and the latter allows enrichment of CARTyrin+ cells using the non-genotoxic drug methotrexate (MTX), leading to greater consistency in patient product material. Characterization of P-BCMA-101 revealed & gt; 70% of cells possessed a stem-cell memory phenotype (i.e. CD45RA+ CCR7+ CD62L+ CD95+) and & gt;95% of the cells were CARTyrin+. In addition, no tonic signaling or T cell exhaustion was observed, highlighted by low levels of PD-1, Lag3, and Tim-3. Cells exhibit specific and robust in vitro target-cell killing, cytokine production, and proliferation in response to BCMA+ tumor cells. In vivo anti-tumor efficacy of P-BCMA-101 has been evaluated in NSG mice bearing luciferase+ MM.1S cells, an aggressive human MM-derived cell line, monitoring tumor growth by bioluminescent imaging (BLI). Following tumor implantation, animals received a single IV administration of either 4 x 106 or 12 x 106 P-BCMA-101 cells. All untreated control animals succumbed to disease within four weeks of the treatment date. Conversely, tumor burden was reduced to the limit of detection by BLI within 7 days of p-BCMA-101 treatment. As opposed to lentivirus-based products in the same animal model, P-BCMA-101 persists and expands in the animals, eliminates tumors from relapse and prolong survival, with most animals surviving 100 days post-tumor implant. Finally, the effectiveness of the safety switch has been demonstrated both in vitro and in vivo. P-BCMA-101 is the first-in-class of Centyrin-based CAR therapeutics modified using PB and is predicted to have improved potency and durability given the phenotype and non-immunogenic properties of Centryrins. We plan to initiate a phase I clinical trial of P-BCMA-101 for the treatment of patients with relapsed and/or refractory MM. Citation Format: David Hermanson, Burton E. Barnett, Srinivas Rengarajan, Rebecca Codde, Christopher E. Martin, Xinxin Wang, Yening Tan, Jenessa B. Smith, Jin He, Rohit Mathur, Sattva S. Neelapu, Jing Yang, Eric M. Ostertag, Shedlock J. Devon. PiggyBac-manufactured anti-BCMA Centyrin-based CAR-T therapeutic exhibits improved potency and durability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3759. doi:10.1158/1538-7445.AM2017-3759

Materialart: Online-Ressource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2017-3759

Sprache: Englisch

Verlag: American Association for Cancer Research (AACR)

Publikationsdatum: 2017

ZDB Id: 2036785-5

ZDB Id: 1432-1

ZDB Id: 410466-3