Monoclonal antibodies and chimeric antigen receptor (CAR) T cells in the treatment of colorectal cancer

AbstractColorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Besides common therapeutic approaches, such as surgery, chemotherapy, and radiotherapy, novel therapeutic approaches, including immunotherapy, have been an advent in CRC treatment. The immunotherapy approaches try to elicit patients` immune responses against tumor cells to eradicate the tumor. Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells are two branches of cancer immunotherapy. MAbs demonstrate the great ability to completely recognize cancer cell-surface receptors and blockade proliferative or inhibitory pathways. On the other hand, T cell activation by genetically engineered CAR receptor via the TCR/CD3 and costimulatory domains can induce potent immune responses against specific tumor-associated antigens (TAAs). Both of these approaches have beneficial anti-tumor effects on CRC. Herein, we review the different mAbs against various pathways and their applications in clinical trials, the different types of CAR-T cells, various specific CAR-T cells against TAAs, and their clinical use in CRC treatment.

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Evaluation of chimeric antigen receptor T cell therapy in non-human primates infected with SHIV or SIV

PLoS ONE ◽

10.1371/journal.pone.0248973 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248973

Author(s):

Nami Iwamoto ◽

Bhavik Patel ◽

Kaimei Song ◽

Rosemarie Mason ◽

Sara Bolivar-Wagers ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Chimeric Antigen Receptor ◽

Viral Suppression ◽

Antigen Receptor ◽

T Cell Therapy ◽

Car T Cells ◽

Car T

Achieving a functional cure is an important goal in the development of HIV therapy. Eliciting HIV-specific cellular immune responses has not been sufficient to achieve durable removal of HIV-infected cells due to the restriction on effective immune responses by mutation and establishment of latent reservoirs. Chimeric antigen receptor (CAR) T cells are an avenue to potentially develop more potent redirected cellular responses against infected T cells. We developed and tested a range of HIV- and SIV-specific chimeric antigen receptor (CAR) T cell reagents based on Env-binding proteins. In general, SHIV/SIV CAR T cells showed potent viral suppression in vitro, and adding additional CAR molecules in the same transduction resulted in more potent viral suppression than single CAR transduction. Importantly, the primary determinant of virus suppression potency by CAR was the accessibility to the Env epitope, and not the neutralization potency of the binding moiety. However, upon transduction of autologous T cells followed by infusion in vivo, none of these CAR T cells impacted either acquisition as a test of prevention, or viremia as a test of treatment. Our study illustrates limitations of the CAR T cells as possible antiviral therapeutics.

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Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer

Journal for ImmunoTherapy of Cancer ◽

10.1186/s40425-017-0222-9 ◽

2017 ◽

Vol 5 (1) ◽

Cited By ~ 67

Author(s):

Kristen M. Hege ◽

Emily K. Bergsland ◽

George A. Fisher ◽

John J. Nemunaitis ◽

Robert S. Warren ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Car T Cells ◽

Car T

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HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer

Cell Death and Disease ◽

10.1038/s41419-021-04100-0 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Jie Xu ◽

Qingtao Meng ◽

Hao Sun ◽

Xinwei Zhang ◽

Jun Yun ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Metastatic Colorectal Cancer ◽

Chimeric Antigen Receptor ◽

Malignant Tumors ◽

Antigen Receptor ◽

Tumor Xenograft ◽

T Cell Therapy ◽

Car T Cells ◽

Car T

AbstractChimeric antigen receptor (CAR) - T cell therapy is a new class of cellular immunotherapies, which has made great achievements in the treatment of malignant tumors. Despite improvements in colorectal cancer (CRC) therapy, treatment of many patients fails because of metastasis and recurrence. The human epidermal growth factor receptor 2 (HER2) is a substantiated target for CAR-T therapy, and has been reported recently to be over-expressed in CRC, which may provide a potential therapeutic target for CRC treatment. Herein, HER2 was a promising target of metastatic colorectal cancer (mCRC) in CAR-T therapy as assessed by flow cytometry and tissue microarray (TMA) with 9-year survival follow-up data. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, through the tumor-bearing model of the NOD-Prkdcem26cd52Il2rgem26Cd22/Nju (NCG) mice, HER2 CAR-T cells showed signs of effectively preventing CRC progression in three different xenograft models. Notably, HER2 CAR-T cells displayed greater aggressiveness in HER2+ CRC in the patient-derived tumor xenograft (PDX) models and had potent immunotherapeutic capacity for mCRC in the metastatic xenograft mouse models. In conclusion, our studies provide scientific evidence that HER2 CAR-T cells represent an emerging immunotherapy for the treatment of mCRC.

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Study of CD 19 Specific Chimeric Antigen Receptor (CAR-T) Cells in ALL and NHL

Case Medical Research ◽

10.31525/ct1-nct04206943 ◽

2019 ◽

Author(s):

Keyword(s):

T Cells ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Car T Cells ◽

Car T

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112 Rational design of chimeric antigen receptor T cells against glypican 3 decouples toxicity from therapeutic efficacy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0112 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A124-A124

Author(s):

Letizia Giardino ◽

Ryan Gilbreth ◽

Cui Chen ◽

Erin Sult ◽

Noel Monks ◽

...

Keyword(s):

T Cells ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Single Chain ◽

High Affinity ◽

Car T Cells ◽

Car T ◽

Animal Care ◽

Cytotoxic Function

BackgroundChimeric antigen receptor (CAR)-T therapy has yielded impressive clinical results in hematological malignancies and it is a promising approach for solid tumor treatment. However, toxicity, including on-target off-tumor antigen binding, is a concern hampering its broader use.MethodsIn selecting a lead CAR-T candidate against the oncofetal antigen glypican 3 (GPC3), we compared CAR bearing a low and high affinity single-chain variable fragment (scFv,) binding to the same epitope and cross-reactive with murine GPC3. We characterized low and high affinity CAR-T cells immunophenotype and effector function in vitro, followed by in vivo efficacy and safety studies in hepatocellular carcinoma (HCC) xenograft models.ResultsCompared to the high-affinity construct, the low-affinity CAR maintained cytotoxic function but did not show in vivo toxicity. High-affinity CAR-induced toxicity was caused by on-target off-tumor binding, based on the evidence that high-affinity but not low-affinity CAR, were toxic in non-tumor bearing mice and accumulated in organs with low expression of GPC3. To add another layer of safety, we developed a mean to target and eliminate CAR-T cells using anti-TNFα antibody therapy post-CAR-T infusion. This antibody functioned by eliminating early antigen-activated CAR-T cells, but not all CAR-T cells, allowing a margin where the toxic response could be effectively decoupled from anti-tumor efficacy.ConclusionsSelecting a domain with higher off-rate improved the quality of the CAR-T cells by maintaining cytotoxic function while reducing cytokine production and activation upon antigen engagement. By exploring additional traits of the CAR-T cells post-activation, we further identified a mechanism whereby we could use approved therapeutics and apply them as an exogenous kill switch that would eliminate early activated CAR-T following antigen engagement in vivo. By combining the reduced affinity CAR with this exogenous control mechanism, we provide evidence that we can modulate and control CAR-mediated toxicity.Ethics ApprovalAll animal experiments were conducted in a facility accredited by the Association for Assessment of Laboratory Animal Care (AALAC) under Institutional Animal Care and Use Committee (IACUC) guidelines and appropriate animal research approval.

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Current Molecular Advancements in Chimeric Antigen Receptor (CAR-T) Cells for the Treatment of Leukemia

Journal of Adolescent and Young Adult Oncology ◽

10.1089/jayao.2021.0102 ◽

2021 ◽

Author(s):

Lavina Ery Paula Bangit ◽

Katarzyna Derwich

Keyword(s):

T Cells ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Car T Cells ◽

Car T

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PSMA targeted armored chimeric antigen receptor (CAR) T-cells in patients with advanced mCRPC: A phase I experience.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2534 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2534-2534

Author(s):

Matthew H. Carabasi ◽

Meredith McKean ◽

Mark N. Stein ◽

Michael Thomas Schweizer ◽

Jason J. Luke ◽

...

Keyword(s):

T Cells ◽

Dose Level ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Dominant Negative ◽

Car T Cells ◽

Car T ◽

Level 1 ◽

Immune Toxicity

2534 Background: CART-PSMA-TGFβRDN cells are autologous T cells engineered via lentiviral transduction to express a dominant negative form of TGFβRII (TGFβRDN) and a chimeric antigen receptor (CAR) with specificity to prostate specific membrane antigen (PSMA). The TGFβRDN renders CAR T cells resistant to TGFβ-mediated immunosuppression. CART-PSMA-02 is a multi-center, open-label, Phase 1 study evaluating the safety and feasibility of dosing patients with metastatic castration resistant prostate cancer (mCRPC) with CART-PSMA-TGFβRDN (NCT04227275). Methods: This is a 3+3 dose escalation study to determine the recommended phase 2 dose and schedule of CART-PSMA-TGFβRDN cells following lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Single and fractionated doses are being evaluated. A cohort expansion will enroll patients to further explore the safety of the selected dose and schedule. Results: As of January 2021, 6 patients (pts) have been treated. Two pts were treated in the first dose level (1-3 x107 transduced T cells (TDN)). Four pts were treated in the second dose level (1-3 x 108 TDN with fractionated dosing). AEs occurring in ≥50 % of pts included cytokine release syndrome (CRS), anemia, thrombocytopenia, increased creatinine, nausea, fatigue, pyrexia and dehydration. No DLTs occurred in the 1st dose level. Four pts in the 2nd dose level developed CRS (3 Gr 1 and 1 Gr 2). One pt developed rapid G2 CRS that progressed to Gr 5 encephalopathy and Gr 5 multi-organ failure. Ferritin levels peaked at 56,974 ng/ml (baseline 2,903 ng/mL) despite aggressive immunosuppressive therapy including tocilizumab, dexamtheasone and anakinra. The post infusion cytokine profile indicated elevations in IL-1RA, TNF-alpha, VEGF, IL-10, MIP-1b, IFN-gamma, GM-CSF and notably lower levels of IL6 compared to published reports of CD19 CART-mediated CRS. Autopsy findings were consistent with HLH/MAS, confirming overactivity of the monocyte/macrophage compartment. Based on these observations, a modified immune toxicity management strategy that includes prophylactic anakinra (an IL1R antagonist) was instituted. Preliminary evidence of clinical activity of CART-PSMA-TGFβRDN was noted in the 2nd dose level. Two of 3 pts with 1 month follow-up demonstrated PSA decreases from baseline (1 with >95% decrease, 1 with >50% decrease). Both pts had stable disease per RECIST v1.1. A third pt with only 1 week follow-up had a 40% PSA decrease. Additional data analyses from all infused patients are ongoing and data from pts managed with modified immune toxicity management will be presented. Conclusions: Initial data indicates a unique immune toxicity profile and the potential for anti-tumor activity in mCRPC pts treated with CART-PSMA-TGFβRDN. Modified immune toxicity management could lead to identification of a manageable safety profile and therapeutically active dose. Clinical trial information: NCT04227275.

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