Abstract 4364: Adenosine A2a receptor blockade as a means of enhancing immune checkpoint inhibition and adoptive T-cell therapy

Immunotherapy, also known as therapy with immune checkpoint inhibitors, has shown good results in the treatment of both solid tumors and hematological malignancies. Patients with diseases that were considered incurable earlier now have an opportunity for long-term disease stabilization and high frequency of clinical remissions. This review focuses on clinical benefits and toxicity profiles of immune checkpoint inhibitors used for cervical cancer, as well as on the ways to improve prognosis and indications for immunotherapy. Correct choice of biomarkers for predicting the response to immunotherapy will ensure more precise selection of patients. This review of immunotherapy methods aims to help clinicians with the indications for this relatively new treatment which has revolutionized treatment standards. Immunotherapy has many forms, including oncolytic virus therapy, chimeric antigen receptor T-cell therapy (CAR), cancer vaccines, and adoptive T-cell therapy, in particular, immune checkpoint inhibitors, first generation of which includes monoclonal antibodies against PD-1 (pembrolizumab, nivolumab, and cemiplimab), against PD-L1 (atezolizumab, avelumab, and durvalumab), and against CTLA-4 protein (ipilimumab).

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Adoptive T Cell Therapy in Patients With Recurrent Ovarian Cancer

Case Medical Research ◽

10.31525/ct1-nct04072263 ◽

2019 ◽

Author(s):

Keyword(s):

Ovarian Cancer ◽

T Cell ◽

Cell Therapy ◽

Recurrent Ovarian Cancer ◽

Adoptive T Cell Therapy ◽

T Cell Therapy

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Enhanced Sensitivity of Lymphoid Cells to Ethanol ADH Acetaldehyde Toxicity; Implications for GDEPT and Adoptive T Cell Therapy

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692116666180703151538 ◽

2018 ◽

Vol 16 (2) ◽

pp. 118-123

Author(s):

Philip Savage ◽

Claire Horlock ◽

Bryony Stott ◽

Justin Stebbing

Keyword(s):

T Cell ◽

Cell Therapy ◽

Lymphoid Cells ◽

Adoptive T Cell Therapy ◽

T Cell Therapy ◽

Enhanced Sensitivity

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'Off-the-shelf’ allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001608 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001608

Author(s):

Debottam Sinha ◽

Sriganesh Srihari ◽

Kirrliee Beckett ◽

Laetitia Le Texier ◽

Matthew Solomon ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Adoptive T Cell Therapy ◽

Nuclear Antigen ◽

T Cell Therapy ◽

In Vivo Models ◽

Hla Alleles ◽

Cell Therapies ◽

Wide Range

BackgroundEpstein-Barr virus (EBV), an oncogenic human gammaherpesvirus, is associated with a wide range of human malignancies of epithelial and B-cell origin. Recent studies have demonstrated promising safety and clinical efficacy of allogeneic ‘off-the-shelf’ virus-specific T-cell therapies for post-transplant viral complications.MethodsTaking a clue from these studies, we developed a highly efficient EBV-specific T-cell expansion process using a replication-deficient AdE1-LMPpoly vector that specifically targets EBV-encoded nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2), expressed in latency II malignancies.ResultsThese allogeneic EBV-specific T cells efficiently recognized human leukocyte antigen (HLA)-matched EBNA1-expressing and/or LMP1 and LMP2-expressing malignant cells and demonstrated therapeutic potential in a number of in vivo models, including EBV lymphomas that emerged spontaneously in humanized mice following EBV infection. Interestingly, we were able to override resistance to T-cell therapy in vivo using a ‘restriction-switching’ approach, through sequential infusion of two different allogeneic T-cell therapies restricted through different HLA alleles. Furthermore, we have shown that inhibition of the programmed cell death protein-1/programmed death-ligand 1 axis in combination with EBV-specific T-cell therapy significantly improved overall survival of tumor-bearing mice when compared with monotherapy.ConclusionThese findings suggest that restriction switching by sequential infusion of allogeneic T-cell therapies that target EBV through distinct HLA alleles may improve clinical response.

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A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽

10.1038/s41375-020-01109-w ◽

2021 ◽

Author(s):

Mohamed-Reda Benmebarek ◽

Bruno L. Cadilha ◽

Monika Herrmann ◽

Stefanie Lesch ◽

Saskia Schmitt ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Cell Therapy ◽

Myeloid Leukemia ◽

Tumor Antigens ◽

Adoptive T Cell Therapy ◽

Single Chain ◽

T Cell Therapy ◽

Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

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Modulation of temozolomide dose differentially affects T-cell response to immune checkpoint inhibition

Neuro-Oncology ◽

10.1093/neuonc/noz015 ◽

2019 ◽

Vol 21 (6) ◽

pp. 730-741 ◽

Cited By ~ 14

Author(s):

Aida Karachi ◽

Changlin Yang ◽

Farhad Dastmalchi ◽

Elias J Sayour ◽

Jianping Huang ◽

...

Keyword(s):

T Cell ◽

Immune Checkpoint ◽

Standard Dose ◽

Antibody Therapy ◽

Tumor Infiltrating Lymphocytes ◽

T Cell Response ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Dose Modulation ◽

Infiltrating Lymphocytes

Abstract Background The changes induced in host immunity and the tumor microenvironment by chemotherapy have been shown to impact immunotherapy response in both a positive and a negative fashion. Temozolomide is the most common chemotherapy used to treat glioblastoma (GBM) and has been shown to have variable effects on immune response to immunotherapy. Therefore, we aimed to determine the immune modulatory effects of temozolomide that would impact response to immune checkpoint inhibition in the treatment of experimental GBM. Methods Immune function and antitumor efficacy of immune checkpoint inhibition were tested after treatment with metronomic dose (MD) temozolomide (25 mg/kg × 10 days) or standard dose (SD) temozolomide (50 mg/kg × 5 days) in the GL261 and KR158 murine glioma models. Results SD temozolomide treatment resulted in an upregulation of markers of T-cell exhaustion such as LAG-3 and TIM-3 in lymphocytes which was not seen with MD temozolomide. When temozolomide treatment was combined with programmed cell death 1 (PD-1) antibody therapy, the MD temozolomide/PD-1 antibody group demonstrated a decrease in exhaustion markers in tumor infiltrating lymphocytes that was not observed in the SD temozolomide/PD-1 antibody group. Also, the survival advantage of PD-1 antibody therapy in a murine syngeneic intracranial glioma model was abrogated by adding SD temozolomide to treatment. However, when MD temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by PD-1 antibody therapy alone. Conclusion The peripheral and intratumoral immune microenvironments are distinctively affected by dose modulation of temozolomide.

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