PET Reporter Gene Imaging and Ganciclovir-Mediated Ablation of Chimeric Antigen Receptor T Cells in Solid Tumors

Chimeric antigen receptor (CAR) T cell therapy has been successful in treating hematological malignancy, but solid tumors remain refractory. Here, we demonstrated that knocking out transcription factor IKZF3 in HER2-specific CAR T cells targeting breast cancer cells did not affect proliferation or differentiation of the CAR T cells in the absence of tumors, but markedly enhanced killing of the cancer cells in vitro and in a xenograft model. Furthermore, IKZF3 KO had similar effects on the CD133-specific CAR T cells targeting glioblastoma cells. AlphaLISA and RNA-seq analyses indicate that IKZF3 KO increased the expression of genes involved in cytokine signaling, chemotaxis and cytotoxicity. Our results suggest a general strategy for enhancing CAR T efficacy on solid tumors.

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The current state of immunotherapy for gliomas: an eye toward the future

Journal of Neurosurgery ◽

10.3171/2019.5.jns181762 ◽

2019 ◽

Vol 131 (3) ◽

pp. 657-666 ◽

Cited By ~ 18

Author(s):

Peter E. Fecci ◽

John H. Sampson

Keyword(s):

T Cells ◽

Solid Tumors ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Checkpoint Blockade ◽

Oncolytic Viruses ◽

Current State ◽

Wide Range ◽

The Future

The last decade has seen a crescendo of FDA approvals for immunotherapies against solid tumors, yet glioblastoma remains a prominent holdout. Despite more than 4 decades of work with a wide range of immunotherapeutic modalities targeting glioblastoma, efficacy has been challenging to obtain. Earlier forms of immune-based platforms have now given way to more current approaches, including chimeric antigen receptor T-cells, personalized neoantigen vaccines, oncolytic viruses, and checkpoint blockade. The recent experiences with each, as well as the latest developments and anticipated challenges, are reviewed.

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Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors

Cancers ◽

10.3390/cancers12102818 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2818

Author(s):

Anna Pasetto

Keyword(s):

T Cells ◽

Solid Tumors ◽

Clinical Application ◽

Nobel Prize ◽

Chimeric Antigen Receptor ◽

Winning Strategy ◽

Antigen Receptor ◽

Check Point ◽

Car T Cells ◽

Car T

In the recent years, immunotherapy has achieved impressive results utilizing different approaches, from (chimeric antigen receptor) CAR-T cells directed against CD19 for the treatment of leukemia and lymphomas to the Nobel prize-winning strategy of check-point inhibition for the treatment of several solid tumors [...]

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Phase I experience with first in class TnMUC1 targeted chimeric antigen receptor T-cells in patients with advanced TnMUC1 positive solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14513 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14513-e14513

Author(s):

Rodolfo Gutierrez ◽

Payal D Shah ◽

Omid Hamid ◽

Alfred L. Garfall ◽

Avery Posey ◽

...

Keyword(s):

T Cells ◽

Phase I ◽

Solid Tumors ◽

Chimeric Antigen Receptor ◽

Dose Escalation ◽

Intracellular Signaling ◽

Antigen Receptor ◽

Low Grade ◽

Gi Symptoms ◽

Dose Levels

e14513 Background: MUC1 is a glycoprotein that is expressed in healthy tissues on the luminal surface of simple and glandular epithelium. In tumors that arise from these cells, an alternate form with aberrant glycosylation is frequently over expressed and distinguishes tumor associated TnMUC1 from normal MUC1. We have generated a novel chimeric antigen receptor (CAR) targeting the TnMUC antigen comprised of a mouse anti-human scFv derived from the monoclonal antibody 5E5 which recognizes the epitope comprising Tn glycan of MUC1, a CD8a transmembrane region and dual CD2 and CD3z intracellular signaling domains. CD2 signaling in T-cells has been demonstrated to result in delayed exhaustion. The novel incorporation of this co-stimulatory domain may lead to enhanced persistence of the CART cells which is believed to be critical for efficacy in solid-tumors. Methods: This is a multi-center first in human Phase I study to evaluate the safety and preliminary efficacy of CART-TnMUC1-Cells for the treatment of solid-tumors. Solid-tumors included in the dose-escalation phase include metastatic treatment-resistant ovarian cancer (OC), pancreatic adenocarcinoma (PC), triple-negative breast cancer (TNBC) or non-small lung cancer (NSCLC). All patients must have TnMUC1 expression as determined by immunohistochemistry. Results: As of January 2021, a total of six patients were treated. Three in Cohort 1 (no lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 OC, 1 TNBC and 1 PC) and 3 in Cohort 2 (flu/cy lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 NSCLC and 2 OC). None of the patients treated experienced DLT’s. The trial is currently enrolling to Cohort 3 (flu/cy lymphodepletion, 5-6 x 107 TDN). No CRS, neurotoxicity, serious adverse reactions and no on-target/off-tumor toxicity was observed at these dose levels. The most common AE’s were low-grade GI symptoms (e.g., nausea, abdominal pain) in 5/6 patients (83.3%), generalized disorders (e.g., chills, fatigue) in 5/6 (83.3%) and hematologic disorders (e.g., anemia, neutropenia) in 3/6 (50%) of patients. CAR expansion was demonstrated in all patients and was improved in Cohort 2 following LD chemotherapy. Preliminary efficacy assessed by RECIST v1.1 at Day +28 demonstrate SD in all patients in Cohort 2. Conclusions: This is the first report of a novel CART-TnMUC1 construct containing a CD2 co-stimulatory domain that has been used in clinical trials for the treatment of refractory solid-tumor malignancies. While the study is still early in dose-escalation having completed only 2 of 6 planned dose levels there is no evidence of safety concerns or on-target/off-tumor toxicity. Additional safety, efficacy and biomarker data is currently being reviewed and will be presented. Clinical trial information: NCT04025216.

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