The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy

Liu, Dongfang; Badeti, Saiaditya; Dotti, Gianpietro; Jiang, Jie‐Gen; Wang, He; Dermody, James; Soteropoulos, Patricia; Streck, Deanna; Birge, Raymond B.; Liu, Chen

doi:10.1186/s12964-020-00617-7

Cited by 34 publications

(34 citation statements)

References 155 publications

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“…Adoptive T cell-based immunotherapy with chimeric antigen receptors (CAR) has shown to be effective for treating refractory blood cancers [ 1 ]. However, predicting the effectiveness of CAR-T cells represents an unsolved problem in the field of immunotherapy [ 2 – 4 ].…”

Section: Introductionmentioning

confidence: 99%

In vitro machine learning-based CAR T immunological synapse quality measurements correlate with patient clinical outcomes

et al. 2022

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The human immune system consists of a highly intelligent network of billions of independent, self-organized cells that interact with each other. Machine learning (ML) is an artificial intelligence (AI) tool that automatically processes huge amounts of image data. Immunotherapies have revolutionized the treatment of blood cancer. Specifically, one such therapy involves engineering immune cells to express chimeric antigen receptors (CAR), which combine tumor antigen specificity with immune cell activation in a single receptor. To improve their efficacy and expand their applicability to solid tumors, scientists optimize different CARs with different modifications. However, predicting and ranking the efficacy of different "off-the-shelf" immune products (e.g., CAR or Bispecific T-cell Engager [BiTE]) and selection of clinical responders are challenging in clinical practice. Meanwhile, identifying the optimal CAR construct for a researcher to further develop a potential clinical application is limited by the current, time-consuming, costly, and labor-intensive conventional tools used to evaluate efficacy. Particularly, more than 30 years of immunological synapse (IS) research data demonstrate that T cell efficacy is not only controlled by the specificity and avidity of the tumor antigen and T cell interaction, but also it depends on a collective process, involving multiple adhesion and regulatory molecules, as well as tumor microenvironment, spatially and temporally organized at the IS formed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. The optimal function of cytotoxic lymphocytes (including CTL and NK) depends on IS quality. Recognizing the inadequacy of conventional tools and the importance of IS in immune cell functions, we investigate a new strategy for assessing CAR-T efficacy by quantifying CAR IS quality using the glass-support planar lipid bilayer system combined with ML-based data analysis. Previous studies in our group show that CAR-T IS quality correlates with antitumor activities in vitro and in vivo. However, current manually quantified IS quality data analysis is time-consuming and labor-intensive with low accuracy, reproducibility, and repeatability. In this study, we develop a novel ML-based method to quantify thousands of CAR cell IS images with enhanced accuracy and speed. Specifically, we used artificial neural networks (ANN) to incorporate object detection into segmentation. The proposed ANN model extracts the most useful information to differentiate different IS datasets. The network output is flexible and produces bounding boxes, instance segmentation, contour outlines (borders), intensities of the borders, and segmentations without borders. Based on requirements, one or a combination of this information is used in statistical analysis. The ML-based automated algorithm quantified CAR-T IS data correlates with the clinical responder and non-responder treated with Kappa-CAR-T cells directly from patients. The results suggest that CAR cell IS quality can be used as a potential composite biomarker and correlates with antitumor activities in patients, which is sufficiently discriminative to further test the CAR IS quality as a clinical biomarker to predict response to CAR immunotherapy in cancer. For translational research, the method developed here can also provide guidelines for designing and optimizing numerous CAR constructs for potential clinical development. Trial Registration: ClinicalTrials.gov NCT00881920.

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Section: Introductionmentioning

confidence: 99%

In vitro machine learning-based CAR T immunological synapse quality measurements correlate with patient clinical outcomes

et al. 2022

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“…Recent preclinical studies of CAR-NK in cancer immunotherapy show several advantages of CAR-NK cells over CAR-T cells in clinical safety. For instance, CAR-NK cells do not present additional risk for the development of severe graft-versus-host-disease (GVHD) (18). More importantly, CAR-NK cells are associated with reduced host cytotoxicity compared to CAR-T cells.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, NK cells are less likely to induce cytokine release syndrome (CRS) that could potentially exacerbate COVID-19 symptoms in severe patients (19). Additionally, CAR-NK cells have potential to be developed as a ‘off-the-shelf’ CAR product in the near future (18, 20, 21). Given these aforementioned reasons, NK and CAR-NK cell-based immunotherapeutics have been rapidly developed for COVID-19 treatment.…”

Section: Introductionmentioning

confidence: 99%

CAR-NK Cells Effectively Target the D614 and G614 SARS-CoV-2-infected Cells

Ma¹,

Badeti²,

Chen³

et al. 2021

Preprint

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious presenting a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants, though the current therapeutic options remain limited and expensive. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet to be documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent antitumor response in hematologic cancers with minimal adverse effects in recent studies, however, the potentials of CAR-NK cells in preventing and treating severe cases of COVID-19 has not yet been fully exploited. Here, we improve upon a novel approach for the generation of CAR-NK cells for targeting SARS-CoV-2 and its D614G mutant. CAR-NK cells were generated using the scFv domain of S309 (henceforward, S309-CAR-NK), a SARS-CoV and SARS-CoV-2 neutralizing antibody that targets the highly conserved region of SARS-CoV-2 spike (S) glycoprotein, therefore would be more likely to recognize different variants of SARS-CoV-2 isolates. S309-CAR-NK cells can specifically bind to pseudotyped SARS-CoV-2 virus and its D614G mutant. Furthermore, S309-CAR-NK cells can specifically kill target cells expressing SARS-CoV-2 S protein in vitro and show superior killing activity and cytokine production, compared to that of the recently published CR3022-CAR-NK cells. Thus, these results pave the way for generating ‘off-the-shelf’ S309-CAR-NK cells for treatment in high-risk individuals as well as provide an alternative strategy for patients unresponsive to current vaccines.

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“…Recent preclinical studies of CAR-NK in cancer immunotherapy show several advantages of CAR-NK cells over CAR-T cells in clinical safety. For instance, CAR-NK cells do not present additional risk for the development of severe graft-versus-hostdisease (GVHD) (18). More importantly, CAR-NK cells are associated with reduced host cytotoxicity compared to CAR-T cells.…”

mentioning

confidence: 99%

“…Specifically, NK cells are less likely to induce cytokine release syndrome (CRS) that could potentially exacerbate COVID-19 symptoms in severe patients (19). Additionally, CAR-NK cells have potential to be developed as a 'off-the-shelf' CAR product in the near future (17,18,20). Given these aforementioned reasons, NK and CAR-NK cell-based immunotherapeutics have been rapidly developed for COVID-19 treatment.…”

mentioning

confidence: 99%

CAR-NK Cells Effectively Target SARS-CoV-2-Spike-Expressing Cell Lines In Vitro

et al. 2021

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent antitumor response in hematologic cancers with minimal adverse effects in recent studies, however, the potentials of CAR-NK cells in treating COVID-19 has not yet been fully exploited. Here, we improve upon a novel approach for the generation of CAR-NK cells for targeting SARS-CoV-2 and its various mutants. CAR-NK cells were generated using the scFv domain of S309 (henceforward, S309-CAR-NK), a SARS-CoV and SARS-CoV-2 neutralizing antibody (NAbs) that targets the highly conserved region of SARS-CoV-2 spike (S) glycoprotein and is therefore more likely to recognize different variants of SARS-CoV-2 isolates. S309-CAR-NK cells can specifically bind to pseudotyped SARS-CoV-2 virus and its D614G, N501Y, and E484K mutants. Furthermore, S309-CAR-NK cells can specifically kill target cells expressing SARS-CoV-2 S protein in vitro and show superior killing activity and cytokine production, compared to that of the recently reported CR3022-CAR-NK cells. Thus, these results pave the way for generating ‘off-the-shelf’ S309-CAR-NK cells for treatment in high-risk individuals as well as provide an alternative strategy for patients unresponsive to current vaccines.

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The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy

Cited by 34 publications

References 155 publications

In vitro machine learning-based CAR T immunological synapse quality measurements correlate with patient clinical outcomes

In vitro machine learning-based CAR T immunological synapse quality measurements correlate with patient clinical outcomes

CAR-NK Cells Effectively Target the D614 and G614 SARS-CoV-2-infected Cells

CAR-NK Cells Effectively Target SARS-CoV-2-Spike-Expressing Cell Lines In Vitro

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