rimiducid (AP1903)

P1, N=60, Active, not recruiting, Poseida Therapeutics, Inc. | Trial primary completion date: Sep 2023 --> Oct 2024

P1, N=42, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=100, Recruiting, Poseida Therapeutics, Inc. | Initiation date: Jan 2024 --> Apr 2024

P1, N=1, Terminated, Bellicum Pharmaceuticals | Active, not recruiting --> Terminated; due to lack of enrollment and changes to the sponsor development portfolio

P1, N=231, Recruiting, Poseida Therapeutics, Inc. | N=135 --> 231 | Trial completion date: Mar 2040 --> Dec 2039 | Trial primary completion date: Jun 2025 --> Dec 2027

P1, N=100, Recruiting, Poseida Therapeutics, Inc. | Not yet recruiting --> Recruiting | N=70 --> 100

P1, N=54, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Apr 2028 --> Apr 2038

P1, N=54, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Oct 2023

P1/2, N=4, Terminated, Bellicum Pharmaceuticals | N=28 --> 4 | Unknown status --> Terminated; company decision

P1, N=54, Not yet recruiting, M.D. Anderson Cancer Center

P1/2, N=187, Terminated, Bellicum Pharmaceuticals | Active, not recruiting --> Terminated; Sponsor decision

P1, N=70, Not yet recruiting, Poseida Therapeutics, Inc.

P1, N=186, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

Expansion of 15.CAR T cells could be rapidly controlled using rimiducid, the inducible caspase 9 (iC9) safety switch alleviating side effects in all three patients that required its use (Figure 1C,D).15.CAR T cells had higher peak expansion than CAR T cells in the peripheral blood (6.77 x 107 vs 3.71 x 103 copy number/mcg DNA; p=0.016), and both groups demonstrated similar levels of tumor trafficking based on transgene qPCR from tumor biopsies (Figure 2A) which was likely due to the early use of iC9 in the 15.CAR group to alleviate AEs resulting lower number of 15.CAR T cells captured post-iC9 use...These results correspond to response rates of 0% for CAR T versus 50% for 15.CAR T treated patients (Figure 2C-E). Based on results from these phase I studies, co-expression of IL15 leads to increased but manageable toxicity with use of the iC9 safety switch, superior expansion of GPC3-CAR T cells resulting in more potent antitumor activity.

P1/2, N=44, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jun 2024 --> Mar 2023 | Trial primary completion date: Jun 2023 --> Mar 2023

P1, N=30, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Oct 2038 --> Mar 2043 | Trial primary completion date: Oct 2023 --> Mar 2027

Considering the favorable effect of this strategy in keeping down the malignant features of the leukemic cells, the effect of the iC9/AP1903 system in combination with all-trans-retinoic acid (ATRA) treatment was evaluated. The obtained data prove that iC9/AP1903 significantly makes the leukemic cells more sensitive to ATRA.

BPX-601, a PSCA-directed GoCAR-T cell product, has preliminary evidence of biologic activity with toxicity characteristic of previously reported CAR-T studies. Markers of rimiducid-induced GoCAR-T cell activation and proliferation were observed. Exploration of escalating weekly rimiducid doses > 0.4 mg/kg and BPX-601 cell doses is planned.

P1/2, N=187, Active, not recruiting, Bellicum Pharmaceuticals | Phase classification: P2 --> P1/2

While early use of corticosteroids (CS) and tocilizumab have improved the management of cytokine release syndrome (CRS), CS are the mainstay of ICANS management...Subjects underwent lymphodepletion with fludarabine and cyclophosphamide followed by infusion of iC9 CAR.19 cells at one of two dose levels (DL1: 5 x 105 CAR-T cells/kg; DL2: 1 x 106 CAR-T cells/kg)... RIM administration to patients with ICANS is associated with abrupt reduction of circulating iC9 CAR.19 cells and ICANS grade. Despite detection of CAR-T cells at 3 weeks post infusion and the observance of remissions after treatment with RIM, further investigation of the effects of RIM on iC9 CAR.19 persistence and antileukemic activity is warranted. Lower, potentially less ablative doses of RIM are being explored.

15.GPC3-CAR T cells can induce robust expansion and antitumor activity and toxicities can be mediated with rimiducid

Patients receive lymphodepletion on Days -4, -3 and -2 with cyclophosphamide and fludarabine followed by T cell infusion on four dose levels (DL1: 3 x 107, 1 x 108, 3 x 108, 1 x 109/m2 CAR+ cells)...This rapid CAR T cell expansion was associated with grade 4 cytokine release syndrome which was not controlled by IL6, IL1 or Tumor necrosis factor-alpha inhibition, but was rapidly relieved by a reduced dose (0.04 mg/kg) of rimiducid, activator of iC9... GPC3-CAR T cells are safe and well tolerated. Results from patient 1 on the AGAR study suggest that co-expression of IL15 with GPC3-CAR in T cells can induce robust expansion and antitumor activity of transduced effectors and that associated toxicities can be mitigated with partial iC9 activation selectively removing the IL15 co-expressing T cell subset.

P1/2, N=36, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2022 --> Jun 2024 | Trial primary completion date: Jun 2022 --> Jun 2023

P1/2, N=105, Terminated, Poseida Therapeutics, Inc. | N=220 --> 105 | Trial completion date: Mar 2024 --> Apr 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2024 --> Apr 2022; Phase I portion of the study was completed. The phase II portion of the study was terminated early to focus on an Allogeneic BCMA CAR-T program.

Patients receive lymphodepletion on Days -4, -3 and -2 with cyclophosphamide and fludarabine followed by T cell infusion on four dose levels (DL1: 3 x 107, 1 x 108, 3 x 108, 1 x 109/m2 CAR+ cells)...This rapid CAR T cell expansion was associated with grade 4 cytokine release syndrome which was not controlled by IL6, IL1 or Tumor necrosis factor-alpha inhibition, but was rapidly relieved by a reduced dose (0.04 mg/kg) of rimiducid, activator of iC9... GPC3-CAR T cells are safe and well tolerated. Results from patient 1 on the AGAR study suggest that co-expression of IL15 with GPC3-CAR in T cells can induce robust expansion and antitumor activity of transduced effectors and that associated toxicities can be mitigated with partial iC9 activation selectively removing the IL15 co-expressing T cell subset.

P1, N=186, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2022 --> Jun 2023 | Trial primary completion date: Jun 2022 --> Jun 2023

P1/2, N=54, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Oct 2036 --> Apr 2041 | Trial primary completion date: Nov 2021 --> Apr 2026

P1/2, N=36, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1/2, N=220, Active, not recruiting, Poseida Therapeutics, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jun 2022 --> Mar 2024 | Trial primary completion date: Dec 2021 --> Mar 2024

The results obtained in the animal model corroborate in vitro data, since iC9.CAR.CD19 tumor cells were controlled in vivo by the activation of the suicide gene through administration of AP1903. Altogether, our data indicate that the inclusion of the iC9 suicide gene may result in a safe CAR-T cell product, even when manufacturing starts from biological materials characterized by heavy leukemia blast contamination.

In order to obtain a safe allogeneic immunotherapy, CAR NK-92MI cells expressing a suicide gene therapy have been generated (99.9% purity) being susceptible to death (near 99% death) upon induction with Rimiducid (AP1903)... CAR NK-92MI effectors expressing single and dual CARs have been generated and they all show higher in vitro antitumor efficacy against different MM targets compared to parental NK-92MI cells. In vivo experiments show the inefficacy of irradiated CAR NK-92MI cells as therapeutic strategy in our MM model, leading to the necessity of a combination with a safety switch to ensure an effective and safe off-the-shelf NK immunotherapy for MM treatment.

P1, N=186, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=36 --> 186

P1, N=36, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2021 --> Jun 2022 | Trial primary completion date: Jun 2021 --> Jun 2022

To settle these drawbacks, CAR NK-92 MI cells expressing suicide gene therapy have been generated (99.8% purity, Figure 1C) and it has been demonstrated that cells can be rapidly eliminated in vitro upon induction with Rimiducid (AP1903)...The co-expression of both CARs results in cytotoxic coverage against different MM targets. In vivo, these data show the futility of irradiation as an NK-92 CAR treatment strategy in our MM model and the further need of combinations with iCasp9 safety switch to ensure the safety and efficacy of the therapy.

We confirmed that the expression of IL-1RAP CAR by an IL-1RAP+ leukemic cell, by decreasing the membrane availability of the targeted antigen, can induce resistance while a high epitope density maintains sensitivity to CAR T cells. Moreover, the presence of the iCASP9/Rimiducid suicide system safety switch makes this immunotherapy approach safe for application in a future phase 1 clinical trial.

P2, N=193, Active, not recruiting, Bellicum Pharmaceuticals | Trial completion date: Dec 2021 --> Feb 2033

We developed a transgene with 4 components: 1) a high-affinity T-cell receptor (TCR) specific for the hematopoietic-restricted minor H antigen, HA-1 that is presented on HLA-A*02:01; 2) a CD8 co-receptor to enhance function of the class I-restricted TCR in CD4+ T cells so they promote cytotoxic CD8+ T cell function and survival; 3) an inducible caspase-9 safety switch, which can be triggered by the drug rimiducid in case of in vivo toxicity; and 4) a CD34-CD20 epitope to facilitate selection of the engineered product during manufacturing and track HA-1 TCR T cells in the recipient...Fludarabine lymphodepletion will be used in most subjects, followed by a single T-cell infusion, with an option for a subsequent infusion(s) if the subject demonstrates an initial response without severe toxicity...The ongoing phase I trial is actively recruiting patients. Development of T-cell immunotherapy targeting other minor H antigen/HLA combinations is also underway to increase the broad applicability of minor H antigen-targeted T-cell immunotherapy.

Activated NK cells were transduced with retrovirus encoding an optimized iMC and IL-15-expressing BCMA CAR construct (iMC-BCMA.z-IL15) where iMC signaling could be activated by exposure to rimiducid (Rim), a small molecule dimerizing ligand...iMC/IL-15-enhanced BCMA GoCAR-NK cells proliferation was associated with improved control of tumor outgrowth in mice challenged with BCMA+ myeloma cells. Summary: These results indicate that the synergistic activity of iMC signaling combined with transgenic IL-15 production can enhance BCMA-specific CAR-NK cytotoxicity, cytokine production, long-term proliferation and persistence and may improve overall anti-tumor efficacy of a potential OTS cell therapy for the treatment of myeloma.

Though most patients with CRS or ICANS experience toxicities that can be managed with supportive care including corticosteroids and tocilizumab, 46% experience grade 3-4 CRS and 13% experience grade 3 ICANS (Maude SL et al N Engl J Med 2018; 37:439)...Subjects underwent lymphodepletion with fludarabine and cyclophosphamide and CAR-T cells were subsequently infused at one of two dose levels (DL1: 5 x 105 CAR-T cells/kg; DL2: 1 x 106 CAR-T cells/kg)...The recommended phase 2 cell dose, 1 x 106 transduced cells/kg is being tested in an expansion cohort. A dose finding study to determine the effects of rimiducid on CRS/ICANS grade, CAR-T cell persistence and cytokine levels is being conducted among expansion cohort patients who experience CRS/ICANS not responding to standard supportive care.

P1/2, N=36, Active, not recruiting, Bellicum Pharmaceuticals | Trial completion date: Dec 2033 --> Nov 2032

P1, N=10, Active, not recruiting, Bellicum Pharmaceuticals | Trial completion date: Dec 2034 --> Jan 2033 | Trial primary completion date: Mar 2018 --> Jan 2020

P1/2, N=120, Active, not recruiting, Bellicum Pharmaceuticals | Phase classification: P2 --> P1/2 | Trial completion date: Feb 2035 --> May 2034 | Trial primary completion date: Feb 2020 --> May 2021