bims-catcri Biomed News
on CAR-T cells, CRISPR and cancer
Issue of 2022–08–07
eleven papers selected by
Lisa Dwane, AstraZeneca
  1. Enhancing co-stimulation of CAR T cells to improve treatment outcomes in solid cancers.
  2. Clinical Investigations of CAR-T Cell Therapy for Solid Tumors.
  3. The role of sex in exhaustion.
  4. Dual-antigen targeted off-the-shelf NK cells show durable response and prevent antigen escape in lymphoma and leukemia.
  5. Emerging approaches for preventing cytokine release syndrome in CAR-T cell therapy.
  6. The efficacy and safety of chimeric antigen receptor T cells in digestive system cancers: a systematic review and meta-analysis.
  7. Engineering Naturally Occurring CD7 Negative T Cells for the Immunotherapy of Hematological Malignancies.
  8. Radiation enhances the efficacy of EGFR-targeted CAR-T cells against triple-negative breast cancer by activating NF-κB/Icam1 signaling.
  9. Adaptable Leukemia Cells Resisting CAR T-cell Attack via B-cell Activation.
  10. Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer.
  11. Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer.
  1. Immunother Adv. 2021 Jan;1(1): ltab016
    Enhancing co-stimulation of CAR T cells to improve treatment outcomes in solid cancers.
    Aaron J Harrison, Xin Du, Bianca von Scheidt, Michael H Kershaw, Clare Y Slaney.
      Co-stimulation is a fundamental component of T cell biology and plays a key role in determining the quality of T cell proliferation, differentiation, and memory formation. T cell-based immunotherapies, such as chimeric antigen receptor (CAR) T cell immunotherapy, are no exception. Solid tumours have largely been refractory to CAR T cell therapy owing to an immunosuppressive microenvironment which limits CAR T cell persistence and effector function. In order to eradicate solid cancers, increasingly sophisticated strategies are being developed to deliver these vital co-stimulatory signals to CAR T cells, often specifically within the tumour microenvironment. These include designing novel co-stimulatory domains within the CAR or other synthetic receptors, arming CAR T cells with cytokines or using CAR T cells in combination with agonist antibodies. This review discusses the evolving role of co-stimulation in CAR T cell therapies and the strategies employed to target co-stimulatory pathways in CAR T cells, with a view to improve responses in solid tumours.
    Keywords:  T cell immunology; chimeric antigen receptor; co-stimulation; immunotherapy
    DOI:  https://doi.org/10.1093/immadv/ltab016
  2. Front Immunol. 2022 ;13 896685
    Clinical Investigations of CAR-T Cell Therapy for Solid Tumors.
    Kun Chen, Shuhang Wang, Dan Qi, Peiwen Ma, Yuan Fang, Ning Jiang, Erxi Wu, Ning Li.
      Cell therapy is a distinguished targeted immunotherapy with great potential to treat solid tumors in the new era of cancer treatment. Cell therapy products include genetically engineered cell products and non-genetically engineered cell products. Several recent cell therapies, especially chimeric antigen receptor (CAR)-T cell therapies, have been approved as novel treatment strategies for cancer. Many clinical trials on cell therapies, in the form of cell therapy alone or in combination with other treatments, in solid tumors, have been conducted or ongoing. However, there are still challenges since adverse events and the limited efficacy of cell therapies have also been observed. Here, we concisely summarize the clinical milestones of the conducted and ongoing clinical trials of cell therapy, introduce the evolution of CARs, discuss the challenges and limitations of these therapeutic modalities taking CAR-T as the main focus, and analyze the disparities in the regulatory policies in different countries.
    Keywords:  cellular immunotherapy; chimeric antigen receptors; genetically engineered; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.896685
  3. Sci Immunol. 2022 Aug 05. 7(74): eade1495
    The role of sex in exhaustion.
    Sarah E Henrickson.
      Androgen receptor signaling promotes CD8 T cell exhaustion that diminishes antitumor immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.ade1495
  4. Blood. 2022 Aug 02. pii: blood.2021015184. [Epub ahead of print]
    Dual-antigen targeted off-the-shelf NK cells show durable response and prevent antigen escape in lymphoma and leukemia.
    Frank Cichocki, Jode Goodridge, Ryan Bjordahl, Sajid Mahmood, Zachary B Davis, Svetlana Gaidarova, Ramzey Abujarour, Brian Groff, Alec Drake Witty, Hongbo Wang, Katie Tuininga, Behiye Kodal, Martin Felices, Gregory B Bonello, Janel Huffman, Thomas Dailey, Tom T Lee, Bruce Walcheck, Bahram Valamehr, Jeffrey S Miller.
      Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell therapy. To overcome antigen escape and address antigen heterogeneity, we engineered induced pluripotent stem cell (iPSC)-derived NK cells to express both an NK cell-optimized anti-CD19 CAR for direct targeting and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity (ADCC). In addition, we introduced a membrane-bound IL-15/IL-15R fusion (IL-15RF) protein to promote in vivo persistence. These engineered cells, termed iDuo NK cells, displayed robust CAR-mediated cytotoxic activity that could be further enhanced with therapeutic antibodies targeting B cell malignancies. In multiple in vitro and xenogeneic adoptive transfer models, iDuo NK cells exhibited robust anti-lymphoma activity. Furthermore, iDuo NK cells effectively eliminated both CD19+ and CD19- lymphoma cells and displayed a unique propensity for targeting malignant cells over healthy cells that expressed CD19, features not achievable with anti-CAR19 T cells. iDuo NK cells combined with therapeutic antibodies represents a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.
    DOI:  https://doi.org/10.1182/blood.2021015184
  5. J Mater Chem B. 2022 Aug 01.
    Emerging approaches for preventing cytokine release syndrome in CAR-T cell therapy.
    Srinivas Balagopal, Koichi Sasaki, Pooja Kaur, Maria Nikolaidi, Jun Ishihara.
      Chimeric antigen receptor (CAR) T cells have demonstrated remarkable anti-tumor efficacy against hematological malignancies, such as leukemia and lymphoma. However, patients treated with CAR-T cells frequently experience cytokine release syndrome (CRS), one of the most life-threatening adverse events of the therapy induced by systemic concentrations of pro-inflammatory cytokines throughout the body. Immunosuppressants such as tocilizumab are currently administered to treat the onset and progression of CRS symptoms. In order to reduce the risk of CRS, newly designed next-generation CAR-T treatments are being developed for both hematopoietic malignancies and solid tumors. In this review, we discuss six classes of interesting approaches that control cytokine production of CAR-T cell therapy: adaptor-based strategies, orthogonal cytokine-receptor pairs, regulation of macrophage cytokine activity, autonomous neutralization of key cytokines, kill switches and methods of reversible suppression of CARs. With these strategies, future CAR-T cell therapies will be designed to preemptively inhibit CRS, minimize the patients' suffering, and maximize the number of benefiting patients.
    DOI:  https://doi.org/10.1039/d2tb00592a
  6. Ann Transl Med. 2022 May;10(9): 508
    The efficacy and safety of chimeric antigen receptor T cells in digestive system cancers: a systematic review and meta-analysis.
    Zijun Zhao, Junwei Zhang, Jin Bian, Xin Lu.
       Background: As a successful treatment for hematological malignancy, chimeric antigen receptor T cells (CAR-T cells) have been expanded to solid tumors to demonstrate their safety and efficacy, especially for digestive system cancer (DSC). Various CAR-T cell constructs used in different types of DSCs result in heterogeneous responses. Thus, we aimed to systematically summarize the clinical response of DSCs treated with CAR-T cells and investigate factors associated with heterogeneity in outcomes.
    Methods: Clinical studies of DSC patients treated with CAR-T cell therapy were selected from the PubMed, Cochrane, Embase, Web of Science databases before October 1, 2020. "CAR-T cell", "solid tumor" and their synonymous terms were used to construct the search strategy. Duplicates, reviews, non-English literature, articles not related to clinical studies or CAR-T cells used for digestive tumors were excluded. The included studies were assessed by the Institute of Health Economics (IHE) risk of bias tool to check the methodological quality. The inverse variance method was used to perform data pooling and subgroup analysis to clarify the causes of heterogeneity. Publication bias was examined by funnel plots and Egger's test.
    Results: Twelve studies were included, and the risk of bias evaluation was demonstrated as plots using Review Manager 5.3. The pooled overall response rate (ORR) was 2% (95% CI: 0-6%), and the clinical benefit rate (CBR) was 42% (95% CI: 24-61%). According to subgroup analysis, costimulation (P=0.0449), lymphodepletion (P=0.0002), persistence of CAR-T cells (P=0.0443) and transduction method (P=0.0165) were factors contributing to heterogeneity. For adverse effects, pyrexia was the most frequent (35%, 95% CI: 24-61%). No publication bias was found, and the major results were robust within a slight fluctuation for each removal of one of the 12 studies.
    Discussion: CAR-T cell therapy is generally beneficial for patients with DSCs though the ORR was still poor. Modified construction with more specific tumor antigens, costimulatory domain and lentiviral vectors is necessary to obtain a better antitumor response of CAR-T cell therapy. Information of survival data are needed for a more comprehensive analysis.
    Keywords:  Chimeric antigen receptor T cell (CAR-T cell); digestive system cancers (DSCs); efficacy; safety; systematic review and meta-analysis
    DOI:  https://doi.org/10.21037/atm-21-5019
  7. Blood. 2022 Aug 01. pii: blood.2021015020. [Epub ahead of print]
    Engineering Naturally Occurring CD7 Negative T Cells for the Immunotherapy of Hematological Malignancies.
    Abdullah Freiwan, Jaquelyn Zoine, Jeremy Chase Crawford, Abishek Vaidya, Stefan A Schattgen, Jacquelyn Myers, Sagar L Patil, Mahsa Khanlari, Hiroto Inaba, Jeffery M Klco, Charles G Mullighan, Giedre Krenciute, Peter Chockley, Swati Naik, Deanna Langfitt, Maksim Mamonkin, Esther A Obeng, Paul G Thomas, Stephen Gottschalk, M Paulina Velasquez.
      Chimeric antigen receptor (CAR) T cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7- T cells to generate CD7-CAR (CD7-CARCD7-)T cells. CD7-CARCD7- T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7- T cells for the immunotherapy of CD19+ hematological malignancies. Direct comparison of non-selected (bulk) CD19-CAR and CD19-CARCD7- T cells revealed that CD19-CARCD7- T cells had enhanced antitumor activity compared to their bulk counterparts in vitro and in vivo. Lastly, to gain insight into the behavior of CD19-CAR T cells with low levels of CD7 gene expression (CD7lo) in humans, we mined single-cell gene and T-cell receptor (TCR) expression data sets from our institutional CD19-CAR T-cell clinical study. CD19-CARCD7lo T cells were present in the initial CD19-CAR T-cell product and could be detected post-infusion. Intriguingly, the only functional CD4+ CD19-CAR T-cell cluster observed post-infusion exhibited CD7lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7lo T cells than in non-responders. Thus, CARCD7- T cells have favorable biological characteristics and may present a promising T-cell subset for adoptive cell therapy of T-ALL and other hematological malignancies.
    DOI:  https://doi.org/10.1182/blood.2021015020
  8. Mol Ther. 2022 Aug 03. pii: S1525-0016(22)00442-7. [Epub ahead of print]
    Radiation enhances the efficacy of EGFR-targeted CAR-T cells against triple-negative breast cancer by activating NF-κB/Icam1 signaling.
    Min Zhou, Muhua Chen, Bizhi Shi, Shengmeng Di, Ruixin Sun, Hua Jiang, Zonghai Li.
      Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited treatment options. Epidermal growth factor receptor (EGFR) is reported to be expressed in 50% to 75% of TNBC patients, making it a promising target for cancer treatment. Here we show that EGFR-targeted Chimeric Antigen Receptor (CAR) T cell therapy combined with radiotherapy provides enhanced antitumor efficacy in immunocompetent and immunodeficient orthotopic TNBC mice. Intriguingly, this combination therapy resulted in a substantial increase in the number of tumor-infiltrating CAR-T cells. The efficacy of this combination was independent of tumor radiosensitivity and lymphodepleting preconditioning. Cytokine profiling showed that this combination did not increase the risk of cytokine release syndrome (CRS). RNA-seq analysis revealed that EGFR-targeting CAR-T therapy combined with radiotherapy increased the infiltration of CD8+ T and NK cells into tumors. Mechanistically, radiation significantly increased Icam1 expression on TNBC cells via activating NF-κB signaling, thereby promoting CAR-T cell infiltration and killing. These results suggest that CAR-T therapy combined with radiotherapy may be a promising strategy for TNBC treatment.
    DOI:  https://doi.org/10.1016/j.ymthe.2022.07.021
  9. Cancer Immunol Res. 2022 Aug 02. OF1
    Adaptable Leukemia Cells Resisting CAR T-cell Attack via B-cell Activation.
    Ziran Zhao, Jan Joseph Melenhorst.
      Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable milestones in the treatment of B-cell malignancies. However, cancer cells frequently survive CAR T-cell killing in a large cohort of patients. Relapse oftentimes is associated with antigen loss. In this issue, Im and colleagues report a new mechanism of leukemic-cell resistance to anti-CD19 CAR T cells: Leukemic cells can enable a B-cell activation and germinal center reaction signature, which causes CD19 transcriptional downregulation and survival from CAR exposure. See related article by Im et al., (5).
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0543
  10. Cancer Immunol Immunother. 2022 Aug 04.
    Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer.
    Jiannan Chen, Jianhua Hu, Lili Gu, Feng Ji, Fan Zhang, Miaomiao Zhang, Jun Li, Zhengliang Chen, Longwei Jiang, Yan Zhang, Ruifang Shi, Lihua Ma, Shaochang Jia, Ying Zhang, Qi Zhang, Junqing Liang, Shunyu Yao, Zhigang Hu, Zhigang Guo.
      Recently, chimeric antigen receptor T cell (CAR-T) therapy has received increasing attention as an adoptive cellular immunotherapy that targets tumors. However, numerous challenges remain for the effective use of CAR-T to treat solid tumors, including ovarian cancer, which is an aggressive and metastatic cancer with a poor therapeutic response. We screened for an effective anti-MSLN single-chain Fv antibody with comparable binding activity and non-off-target properties using human phage display library. A second-generation of anti-MSLN CAR was designed and generated. We demonstrated the efficacy of our anti-MSLN CAR-T cells for ovarian cancer treatment in an in vitro experiment to kill ovarian tumor cell lines. The anti-MSLN CAR-T cells impeded MSLN-positive tumor growth concomitant with a significant increase in cytokine levels compared with the control. Then, we demonstrated the efficacy of anti-MSLN CAR-T cells in an in vivo experiment against ovarian cancer cell-derived xenografts. Furthermore, we herein report three cases with ovarian cancer who were treated with autologous anti-MSLN CAR-T cells and evaluate the safety and effectiveness of adoptive cell therapy. In this investigator-initiated clinical trials, no patients experienced cytokine release syndrome or neurological symptoms over 2 grads. Disease stabilized in two patients, with progression-free survival times of 5.8 and 4.6 months. Transient CAR expression was detected in patient blood after infusion each time. The tumor partially subsided, and the patient's condition was relieved. In conclusion, this work proves the efficacy of the anti-MSLN CAR-T treatment strategy in ovarian cancer and provides preliminary data for the development of further clinical trials.
    Keywords:  CAR-T; Immunotherapy; Investigator-initiated clinical trial; Mesothelin; Ovarian cancer
    DOI:  https://doi.org/10.1007/s00262-022-03238-w
  11. Immunother Adv. 2022 ;2(1): ltac005
    Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer.
    Rafaela Rossetti, Heloísa Brand, Sarah Caroline Gomes Lima, Izadora Peter Furtado, Roberta Maraninchi Silveira, Daianne Maciely Carvalho Fantacini, Dimas Tadeu Covas, Lucas Eduardo Botelho de Souza.
      Immune checkpoint (IC) blockade using monoclonal antibodies is currently one of the most successful immunotherapeutic interventions to treat cancer. By reinvigorating antitumor exhausted T cells, this approach can lead to durable clinical responses. However, the majority of patients either do not respond or present a short-lived response to IC blockade, in part due to a scarcity of tumor-specific T cells within the tumor microenvironment. Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) provide the necessary tumor-specific immune cell population to target cancer cells. However, this therapy has been considerably ineffective against solid tumors in part due to IC-mediated immunosuppressive effects within the tumor microenvironment. These limitations could be overcome by associating adoptive cell transfer of genetically engineered T cells and IC blockade. In this comprehensive review, we highlight the strategies and outcomes of preclinical and clinical attempts to disrupt IC signaling in adoptive T-cell transfer against cancer. These strategies include combined administration of genetically engineered T cells and IC inhibitors, engineered T cells with intrinsic modifications to disrupt IC signaling, and the design of CARs against IC molecules. The current landscape indicates that the synergy of the fast-paced refinements of gene-editing technologies and synthetic biology and the increased comprehension of IC signaling will certainly translate into a novel and more effective immunotherapeutic approaches to treat patients with cancer.
    Keywords:  cancer immunotherapy; chimeric antigen receptor; engineered T cells; gene editing; immune checkpoint inhibitors
    DOI:  https://doi.org/10.1093/immadv/ltac005
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