Novel Gamma-Delta (γδ)T Cell Therapy for Treatment of Patients With Newly Diagnosed Glioblastoma

TPS3150 Background: Temozolomide (TMZ) transiently upregulates GBM-specific stress-induced NKG2D ligands that are targeted by innate immune effector cells. Leveraging this effect is problematic, however, due to the lymphodepleting effects of TMZ.Genetic modification of ex vivo expanded and activated with an MGMT-expressing lentivector allows simultaneous chemotherapy and γδ T cell therapy that targets the tumor when NKG2DL are maximally expressed. We have termed this Drug Resistant Immunotherapy (DRI). Patient-derived xenograft mouse models of both primary and recurrent GBM treated with DRI have shown a significant survival advantage that were otherwise impervious to either cell therapy or TMZ. These preclinical findings and associated safety data provide the rationale to initiate a Phase I trial of DRI in primary GBM. Methods: This first in human study will evaluate the safety and optimal dosing frequency of the DRI with TMZ (NCT04165941).Eligibility criteria include the following: GBM eligible for resection, ≥18y, adequate organ and marrow function, and KPS≥70. Six to 12patients with newly diagnosed GBM are being enrolled in a 3 + 3 design into 1 of 2 fixed dose levels (DL) of DRI. Following tumor resection and immediately prior to induction chemo/radiotherapy, an apheresis product is collected and γδ T cells expanded in Zoledronic Acid (Novartis) and rhIL-12 (Miltenyi) and transduced with a P140K-MGMT lentivector (Miltenyi Lentigen, Gaithersburg, MD), harvested, and cryopreserved. At initiation of maintenance phase TMZ therapy, patients receive 150mg/m2 intravenous TMZ concurrently with intracranial injection of 1 x 107 γδ T cells (DL1) delivered through a Rickham reservoir previously inserted into the tumor cavity at resection. The patient then receives 4 daily doses of oral TMZ followed by 24d rest. Treatment cycles escalate from 1 to 3 (DL2) DRI doses following a safety observation period and absence of dose limiting toxicity. Maintenance TMZ treatment will continue for 6 cycles. Safety evaluations consist of routine laboratory analyses, clinical measurements (physical exams, vital signs), neurological function and evidence DRI γδ T cell related toxicity. Peripheral blood will be obtained for comprehensive immuno-phenotyping and T cell function analysis. Clinical benefit of DRI will be characterized by evaluating responses (CR, PR, SD and PD) and determining progression-free, median, and overall survival. As of February 2020, enrollment into DL 1 is ongoing. Clinical trial information: NCT04165941 .

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KarMMa-4: Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy in high-risk newly diagnosed multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps8053 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS8053-TPS8053

Author(s):

Saad Z. Usmani ◽

Jesus G. Berdeja ◽

Anna Truppel-Hartmann ◽

Yizhou Fei ◽

Honeylet Wortman-Vayn ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Cell Therapy ◽

Stage Iii ◽

Newly Diagnosed ◽

Target Dose ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

TPS8053 Background: High-risk (R-ISS stage III) newly diagnosed multiple myeloma (NDMM) has a poor prognosis (median PFS, 29 mo), highlighting the need for novel disease-targeting approaches (Palumbo A, et al. J Clin Oncol 2015;33:2863-2869). Ide-cel, a BCMA-directed CAR T cell therapy, demonstrated deep, durable responses in heavily pretreated patients (pts) with relapsed and refractory MM (RRMM; Raje N, et al. N Engl J Med 2019;380:1726-1737; Munshi NC, et al. J Clin Oncol 2020;38[suppl 15]. Abstract 8503), including those with high-risk (R-ISS stage III) RRMM. In this population, earlier use of ide cel—when there may be more bone marrow reserve, more healthy peripheral blood mononuclear cells, a less compromised immune status, and less extensive disease to debulk before cell therapy—may result in improved outcomes vs standard therapies and offer an opportunity to replace transplant with CAR T cell therapy. Methods: KarMMa-4 (NCT04196491), a multicenter, open-label, phase 1, single-arm study, is currently evaluating ide-cel in pts with high-risk NDMM, defined as R-ISS stage III (ISS stage III [serum ß2 microglobulin ≥ 5.5 mg/L] and cytogenetic abnormalities t(4;14), del(17p), and/or t(14;16) by interphase FISH; or ISS stage III and serum LDH > ULN). Pts must have received ≤ 3 cycles of the induction regimens listed below, be aged ≥ 18 years, and have ECOG PS 0-1. Nonsecretory MM and CNS involvement are exclusion criteria. Pts can enroll between induction cycles 1 and 3. Permitted cycle 1 regimens are carfilzomib + lenalidomide (LEN) + dexamethasone (DEX) ± daratumumab (DARA; KRd ± DARA), LEN + bortezomib (BOR) + DEX ± DARA (RVd ± DARA), or cyclophosphamide + BOR + DEX (CyBorD). Induction cycles 2-4 are limited to KRd or RVd, with DEX omitted during cycle 3. Pts will undergo T cell collection via leukapheresis after cycle 3, and ide-cel will be manufactured during cycle 4. Stem cell collection for future use may be conducted after cycle 3 (following leukapheresis) or 4 (before lymphodepletion). Ide-cel is infused after 2 days of rest following lymphodepletion with 3 days of fludarabine 30 mg/m2 + cyclophosphamide 300 mg/m2. LEN-based maintenance may be provided upon bone marrow recovery or 90 days after ide-cel infusion, whichever is later. Dose-limiting toxicity and safety are the primary endpoints. Secondary endpoints include complete response (CR) rate and overall response rate, duration of response, time to CR, time to start of maintenance, feasibility of initiating maintenance, PFS, overall survival, and pharmacokinetics. Exploratory endpoints include LEN maintenance safety, minimal residual disease, immunogenicity and biomarkers. The starting ide-cel target dose is 450 × 106 CAR+ T cells, with dose escalation/de-escalation (150, 300, and 800 × 106 CAR+ T cells). Upon determination of optimal target dose, 12 pts will be enrolled in the dose-expansion phase. Clinical trial information: NCT04196491.

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Gamma Delta T Cell Therapy for Cancer: It Is Good to be Local

Frontiers in Immunology ◽

10.3389/fimmu.2018.01305 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 35

Author(s):

C. David Pauza ◽

Mei-Ling Liou ◽

Tyler Lahusen ◽

Lingzhi Xiao ◽

Rena G. Lapidus ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Gamma Delta ◽

T Cell Therapy ◽

Gamma Delta T Cell

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Study of BiRd Regimen Combined With BCMA CAR T-cell Therapy in Newly Diagnosed Multiple Myeloma (MM) Patients

Case Medical Research ◽

10.31525/ct1-nct04287660 ◽

2020 ◽

Author(s):

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Cell Therapy ◽

Newly Diagnosed ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

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Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003441 ◽

2021 ◽

Vol 9 (12) ◽

pp. e003441

Author(s):

Amani Makkouk ◽

Xue (Cher) Yang ◽

Taylor Barca ◽

Anthony Lucas ◽

Mustafa Turkoz ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

T Cell ◽

Antitumor Activity ◽

Cell Therapy ◽

Solid Tumors ◽

Chimeric Antigen Receptor ◽

Gamma Delta ◽

T Cell Therapy ◽

Cell Therapies

BackgroundGlypican-3 (GPC-3) is an oncofetal protein that is highly expressed in various solid tumors, but rarely expressed in healthy adult tissues and represents a rational target of particular relevance in hepatocellular carcinoma (HCC). Autologous chimeric antigen receptor (CAR) αβ T cell therapies have established significant clinical benefit in hematologic malignancies, although efficacy in solid tumors has been limited due to several challenges including T cell homing, target antigen heterogeneity, and immunosuppressive tumor microenvironments. Gamma delta (γδ) T cells are highly cytolytic effectors that can recognize and kill tumor cells through major histocompatibility complex (MHC)-independent antigens upregulated under stress. The Vδ1 subset is preferentially localized in peripheral tissue and engineering with CARs to further enhance intrinsic antitumor activity represents an attractive approach to overcome challenges for conventional T cell therapies in solid tumors. Allogeneic Vδ1 CAR T cell therapy may also overcome other hurdles faced by allogeneic αβ T cell therapy, including graft-versus-host disease (GvHD).MethodsWe developed the first example of allogeneic CAR Vδ1 T cells that have been expanded from peripheral blood mononuclear cells (PBMCs) and genetically modified to express a 4-1BB/CD3z CAR against GPC-3. The CAR construct (GPC-3.CAR/secreted interleukin-15 (sIL)-15) additionally encodes a constitutively-secreted form of IL-15, which we hypothesized could sustain proliferation and antitumor activity of intratumoral Vδ1 T cells expressing GPC-3.CAR.ResultsGPC-3.CAR/sIL-15 Vδ1 T cells expanded from PBMCs on average 20,000-fold and routinely reached >80% purity. Expanded Vδ1 T cells showed a primarily naïve-like memory phenotype with limited exhaustion marker expression and displayed robust in vitro proliferation, cytokine production, and cytotoxic activity against HCC cell lines expressing low (PLC/PRF/5) and high (HepG2) GPC-3 levels. In a subcutaneous HepG2 mouse model in immunodeficient NSG mice, GPC-3.CAR/sIL-15 Vδ1 T cells primarily accumulated and proliferated in the tumor, and a single dose efficiently controlled tumor growth without evidence of xenogeneic GvHD. Importantly, compared with GPC-3.CAR Vδ1 T cells lacking sIL-15, GPC-3.CAR/sIL-15 Vδ1 T cells displayed greater proliferation and resulted in enhanced therapeutic activity.ConclusionsExpanded Vδ1 T cells engineered with a GPC-3 CAR and sIL-15 represent a promising platform warranting further clinical evaluation as an off-the-shelf treatment of HCC and potentially other GPC-3-expressing solid tumors.

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