Kooperativer Bibliotheksverbund

In: Infection and Immunity, American Society for Microbiology, Vol. 75, No. 5 ( 2007-05), p. 2291-2296

Abstract: Help from CD4 T cells is often important for the establishment of primary and memory CD8 T-cell responses. However, it has yet to be determined whether T helper polarization affects the delivery of help and/or whether responding CD8 T cells helped by Th1 or Th2 cells express distinct effector properties. To address these issues, we compared CD8 T-cell responses in the context of Th1 or Th2 help by injecting dendritic cells copulsed with the major histocompatibility complex class I-restricted OVA peptide plus, respectively, bacterial or helminth antigens. We found that Th2 cells, like Th1 cells, can help primary and long-lived memory CD8 T-cell responses. Experiments in interleukin-12 (IL-12) −/− and IL-4 −/− mice, in which polarized Th1 or Th2 responses, respectively, fail to develop, indicate that the underlying basis of CD4 help is independent of attributes acquired as a response to polarization.

Type of Medium: Online Resource

ISSN: 0019-9567 , 1098-5522

URL: Article

DOI: 10.1128/IAI.01328-06

Language: English

Publisher: American Society for Microbiology

Publication Date: 2007

detail.hit.zdb_id: 1483247-1

In: Immunology, Wiley, Vol. 128, No. 1pt2 ( 2009-09), p. e612-e620

Type of Medium: Online Resource

ISSN: 0019-2805 , 1365-2567

URL: Issue

URL: Article

DOI: 10.1111/imm.2009.128.issue-1pt2

DOI: 10.1111/j.1365-2567.2009.03044.x

Language: English

Publisher: Wiley

Publication Date: 2009

detail.hit.zdb_id: 2006481-0

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

Abstract: 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.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.PRCA2017-A071

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. 138, No. Supplement 1 ( 2021-11-05), p. 4802-4802

Abstract: 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-154034

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1012-1012

Abstract: P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell therapeutic targeting BCMA, which is highly expressed on MM cells. It is designed to increase efficacy while minimizing toxicity through reduced immunogenicity, lack of tonic signaling, a safety switch, and a product comprised predominantly of early memory T cells that are effectively all CAR-positive. Rather than using a traditional antibody-based binder, P-BCMA-101 utilizes an anti-BCMA Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human and have high binding affinities, but are smaller, more stable and potentially less immunogenic. P-BCMA-101 is produced using the piggyBac™ (PB) DNA Modification System instead of a viral vector, and requires only plasmid DNA and mRNA. This eliminates the need for virus, is less costly, and produces a purified population of CAR+ cells with a preponderance of the favorable stem cell memory T phenotype (TSCM). The higher cargo capacity permits the incorporation of other genes, a safety switch that allows for rapid depletion of product in vivo if indicated by adverse events, and a selection gene that allows for enrichment of CAR+ cells. These features are predicted to result in a greater 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 without re-administration of product. A Phase 1, 3+3 dose escalation 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 as a single intravenous (IV) dose after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. As of 31Jul18, 12 patients have been treated with 48, 50, 55, 118, 122, 124, 143, 155, 164, 238, 324 and 430 x 106 P-BCMA-101 CAR-T cells in 3 weight-based cohorts. Patients were heavily pre-treated (3-9 prior therapies), 100% had failed IMiDs, proteasome inhibitors and daratumumab, and 64% had high-risk cytogenetics. Nine patients have yet reached their first 2-week response assessment. All patients have shown some improvement in myeloma assessments on study, yet only 1 patient (8%) has developed any cytokine release syndrome (CRS) (limited Grade 2). Of 3 patients in the first cohort 1 attained a PR and 1 with non-secretory disease near CR of her plasmacytomas on PET/CT. Of the subsequent 6 patients, 3 patients have thus far reached a PR, 1 a VGPR, and 1 a sCR. Thus of the yet evaluable patients treated above Cohort 1, the overall response rate (ORR) is 83% (5/6), in spite of only one experiencing CRS. This CRS was scored as Grade 2, based on short-lived fever and hypotension managed with IV fluids and antibiotics, with minimal CRS marker elevations. Likewise, CRS markers were minimally elevated in other patients. The maximal IL-6 level in any patient was 86 pg/mL, which is orders of magnitude lower than levels generally reported in patients experiencing meaningful CRS after treatment with CAR-T products. No patients required treatment with tocilizumab or safety switch activation. There have been no patient deaths, and no neurotoxicity, DLTs or unexpected/off-target toxicities related to treatment. Generally, infusions were well-tolerated, with cytopenias, including transfusion requiring cytopenias and febrile neutropenia, being the most common Grade 3+ adverse events. Consistent with the hypothesis of the early memory phenotype conveying durability, circulating P-BCMA-101 cells were detected in the blood by flow and PCR, peaking at 2-3 weeks, and remaining detectable at the last timepoint tested in all patients (3 patients thus far assessed at 3 months). In conclusion, current clinical trial data in patients with r/r MM support preclinical findings that the novel design of P-BCMA-101 can produce significant efficacy, comparing favorably with other anti-BCMA CAR-T products at similar doses, with notably less CRS and no neurotoxicity, consistent with the hypothesis of an improved therapeutic index. Funding by Poseida Therapeutics and CIRM. Disclosures Gregory: Poseida Therapeutics, Inc.: Research Funding. Cohen:Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Oncopeptides: Consultancy; Poseida Therapeutics, Inc.: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Novartis: Research Funding. Costello:Celgene: Consultancy; Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy. Ali:Celgene Inc: Research Funding; Aduro Biotech: Consultancy, Research Funding; Amgen Inc: Consultancy; Juno: Consultancy; Takeda Oncology: Consultancy; Poseida Therapeutics: Research Funding. Berdeja:Genentech: Research Funding; Bluebird: Research Funding; Glenmark: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Teva: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Resler:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Millenium Pharmaceuticals: Consultancy, Research Funding; Poseida: Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-111419

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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. 4557-4557

Abstract: Chimeric-antigen receptor (CAR)-T cell immunotherapy is a promising type of cancer therapy and substantial progress has been made in developing adoptive T cell approaches for B cell malignancies. B cell maturation antigen (BCMA) is an attractive target for patients with multiple myeloma (MM) due to its high level of expression on tumor cells and restricted expression on normal tissues. Traditionally, the antigen-binding domain of a CAR is a single chain variable fragment (scFv) comprised of heavy chain (HC) and light chain (LC) variable fragments joined by a flexible linker that has been derived from a non-human monoclonal Ab (mAb). However, there are a number of disadvantages to scFv-based CARs including the limited availability of scFv, their potential to elicit antibody responses, and their association with tonic signaling due, in part, to inherent instability and flexibility of the structure and the potential for both HC/LC domain swapping and multimer formation through framework region interactions. Thus, replacement with alternative binding technologies may improve CAR-T efficacy in the clinic. Centyrins are alternative scaffold molecules that bind protein targets with high affinity and specificity, similar to scFv molecules. However, unlike scFv, Centyrins are smaller, derived from human consensus tenascin FN3 domains and are predicted to have decreased immunogenicity. Additionally, a monomeric Centryin in CAR format (i.e. CARTyrin molecule) is less likely to engage in domain swapping or interact with other Centyrins at the cell surface, thereby limiting the potential for the tonic signaling that drives the functional exhaustion of CAR T cells. Centyrins can be isolated against virtually any antigen through ex vivo panning of an extensive Centyrin library, yielding many distinct binders with a range of affinities and target epitopes. Panning with soluble BCMA protein yielded a large pool of BCMA-specific Centyrins, from which 11 distinct monomeric binders and 1 non-monomeric binder were selected for further study in CAR format. In addition, we tested numerous signal peptides, linkers, transmembrane domains and signaling domains to determine optimal configuration. We then created all CARTyrins by fusing each Centyrin with a CD8a leader peptide, spacer and transmembrane domain, as well as an intracellular signaling domain derived from both 4-1BB and CD3ζ. High quality mRNA of each CARTyrin construct was produced in order to rapidly screen CARTyrin cell surface expression and functionality in human pan T cells against BCMA+ targets. We also constructed scFv-based CARs against CD19 and BCMA for comparison. Previously CD3/CD28-stimulated T cells were electroporated (EP) with mRNA encoding each of the 12 anti-BCMA CARTyrins and, the following day, analyzed for surface expression of CARTyrin and their ability to degranulate against BCMA+ tumor cells. All 12 CARTyrins were detected on the cell surface and the 11 monomeric CARTyrins imparted BCMA-specific killing capacity to T cells. Notably, in these assays, CARTyrins were functionally comparable to scFv-based CARs against BCMA or to CD19-specific scFv-based CARs in a parallel assay with CD19+ tumor cells. The 11 functional anti-BCMA CARTyrins were further characterized for functional avidity by determining their activity against a panel of target cells with titrated levels of surface BCMA expression. To create this panel, various amounts of high quality BCMA mRNA were electroporated into BCMA- K562 tumor cells. After 4 hours of co-culture with the panel of BCMA expressing cells, CARTyrin+ T cell activity was measured as a function of CD107a expression. We observed a range of activities by each CARTyrin and show that this assay can be utilized to determine the minimal effective dose of BCMA needed to induce killing by CARTyrin+ cells. Furthermore, we establish that certain BCMA-specific CARTyrins are responsive to target cells with extremely low levels of surface BCMA expression. These results confirm that Centyrins are viable replacements for scFv in the construction of functional CARs and establish their potential utility in generating novel BCMA-specific CAR molecules, as well as other novel targetable tumor antigens. Disclosures Barnett: Poseida Therapeutics: Employment. Wang:Poseida Therapeutics: Employment. Hermanson:Poseida Therapeutics: Employment. Tan: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.V128.22.4557.4557

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.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

Abstract: 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.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2022.40.6_suppl.098

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2022

detail.hit.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

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: The Journal of Immunology, The American Association of Immunologists, Vol. 173, No. 4 ( 2004-08-15), p. 2494-2499

Abstract: Classical CD4+ and CD8+ T cells recognize Ag presented by MHC class II (MHCII) and MHC class I (MHCI), respectively. However, our results show that CD4−/− mice mount a strong, readily detectable CD8+ T cell response to MHCII-restricted epitopes after a primary bacterial or viral infection. These MHCII-restricted CD8+CD4− T cells are more similar to classical CD8+ T cells than to CD4+ T cells in their expression of effector functions during a primary infection, yet they also differ from MHCI-restricted CD8+ T cells by their inability to produce high levels of the cytolytic molecule granzyme B. After resolution of a primary infection, epitope-specific MHCII-restricted T cells in CD4−/− mice persist for a long period of time as memory T cells. Surprisingly, upon reinfection the secondary MHCII-restricted response in CD4−/− mice consists mainly of CD8−CD4− T cells. In contrast to CD8+ T cells, MHCII-restricted CD8−CD4− T cells are capable of producing IL-2 in addition to IFN-γ and thus appear to have attributes characteristic of CD4+ T cells rather than CD8+ T cells. Therefore, MHCII-restricted T cells in CD4−/− mice do not share all phenotypic and functional characteristics with MHCI-restricted CD8+ T cells or with MHCII-restricted CD4+ T cells, but, rather, adopt attributes from each of these subsets. These results have implications for understanding thymic T cell selection and for elucidating the mechanisms regulating the peripheral immune response and memory differentiation.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.173.4.2494

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2004

detail.hit.zdb_id: 1475085-5