bims-catcri Biomed News
on CAR-T cells, CRISPR and cancer
Issue of 2022–07–31
twelve papers selected by
Lisa Dwane, AstraZeneca
  1. Challenges in the Treatment of Glioblastoma by Chimeric Antigen Receptor T-Cell Immunotherapy and Possible Solutions.
  2. Revolution of CAR Engineering For Next-Generation Immunotherapy In Solid Tumors.
  3. T cell receptor β-chain-targeting chimeric antigen receptor T cells against T cell malignancies.
  4. CAR T-Cell Therapy Predictive Response Markers in Diffuse Large B-Cell Lymphoma and Therapeutic Options After CART19 Failure.
  5. From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer.
  6. FGFR4-targeted chimeric antigen receptors (CARs) combined with anti-myeloid poly-pharmacy effectively treats orthotopic rhabdomyosarcoma.
  7. Adoptive Cellular Therapy for Pediatric Solid Tumors: Beyond Chimeric Antigen Receptor-T Cell Therapy.
  8. Identification of genomic determinants contributing to cytokine release in immunotherapies and human diseases.
  9. Modulation of BCL-2 in both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T cell Immunotherapy against Cancer.
  10. PARP11 interfer(on)es with CAR T cell efficacy.
  11. CD8 T cell heterogeneity during T cell exhaustion and PD-1-targeted immunotherapy.
  12. NK Cell-Based Immunotherapy in Colorectal Cancer.
  1. Front Immunol. 2022 ;13 927132
    Challenges in the Treatment of Glioblastoma by Chimeric Antigen Receptor T-Cell Immunotherapy and Possible Solutions.
    Peng Zhang, Yang Zhang, Nan Ji.
      Glioblastoma (GBM), one of the most lethal brain cancers in adults, accounts for 48.6% of all malignant primary CNS tumors diagnosed each year. The 5-year survival rate of GBM patients remains less than 10% even after they receive the standard-of-care treatment, including maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide. Therefore, new therapeutic modalities are urgently needed for this deadly cancer. The last decade has witnessed great advances in chimeric antigen receptor T (CAR-T) cell immunotherapy for the treatment of hematological malignancies. Up to now, the US FDA has approved six CAR-T cell products in treating hematopoietic cancers including B-cell acute lymphoblastic leukemia, lymphoma, and multiple myeloma. Meanwhile, the number of clinical trials on CAR-T cell has increased significantly, with more than 80% from China and the United States. With its achievements in liquid cancers, the clinical efficacy of CAR-T cell therapy has also been explored in a variety of solid malignancies that include GBMs. However, attempts to expand CAR-T cell immunotherapy in GBMs have not yet presented promising results in hematopoietic malignancies. Like other solid tumors, CAR-T cell therapies against GBM still face several challenges, such as tumor heterogeneity, tumor immunosuppressive microenvironment, and CAR-T cell persistence. Hence, developing strategies to overcome these challenges will be necessary to accelerate the transition of CAR-T cell immunotherapy against GBMs from bench to bedside.
    Keywords:  CAR-T; adoptive immunotherapy; cellular immunotherapy; chimeric antigen receptor; glioblastoma
    DOI:  https://doi.org/10.3389/fimmu.2022.927132
  2. Front Immunol. 2022 ;13 936496
    Revolution of CAR Engineering For Next-Generation Immunotherapy In Solid Tumors.
    Tao Yu, Shao-Kun Yu, Yan Xiang, Kai-Hua Lu, Ming Sun.
      Chimeric antigen receptor (CAR)-T cells have enormous potentials for clinical therapies. The CAR-T therapy has been approved for treating hematological malignancies. However, their application is limited in solid tumors owing to antigen loss and mutation, physical barriers, and an immunosuppressive tumor microenvironment. To overcome the challenges of CAR-T, increasing efforts are put into developing CAR-T to expand its applied ranges. Varied receptors are utilized for recognizing tumor-associated antigens and relieving immunosuppression. Emerging co-stimulatory signaling is employed for CAR-T activation. Furthermore, other immune cells such as NK cells and macrophages have manifested potential for delivering CAR. Hence, we collected and summarized the last advancements of CAR engineering from three aspects, namely, the ectodomains, endogenous domains, and immune cells, aiming to inspire the design of next-generation adoptive immunotherapy for treating solid tumors.
    Keywords:  CAR-T cells; co-stimulatory domains; cytokine; immune cells; receptors; solid tumor
    DOI:  https://doi.org/10.3389/fimmu.2022.936496
  3. Nat Commun. 2022 Jul 26. 13(1): 4334
    T cell receptor β-chain-targeting chimeric antigen receptor T cells against T cell malignancies.
    Fanlin Li, Huihui Zhang, Wanting Wang, Puyuan Yang, Yue Huang, Junshi Zhang, Yaping Yan, Yuan Wang, Xizhong Ding, Jie Liang, Xinyue Qi, Min Li, Ping Han, Xiaoqing Zhang, Xin Wang, Jiang Cao, Yang-Xin Fu, Xuanming Yang.
      The success of chimeric antigen receptor (CAR) T cells in treating B cell malignancies comes at the price of eradicating normal B cells. Even though T cell malignancies are aggressive and treatment options are limited, similar strategies for T cell malignancies are constrained by the severe immune suppression arising from bystander T cell aplasia. Here, we show the selective killing of malignant T cells without affecting normal T cell-mediated immune responses in vitro and in a mouse model of disseminated leukemia. Further, we develop a CAR construct that carries the single chain variable fragment of a subtype-specific antibody against the variable TCR β-chain region. We demonstrate that these anti-Vβ8 CAR-T cells are able to recognize and kill all Vβ8+ malignant T cells that arise from clonal expansion while sparing malignant or healthy Vβ8- T cells, allowing sufficient T cell-mediated cellular immunity. In summary, we present a proof of concept for a selective CAR-T cell therapy to eradicate T cell malignancies while maintaining functional adaptive immunity, which opens the possibility for clinical development.
    DOI:  https://doi.org/10.1038/s41467-022-32092-8
  4. Front Immunol. 2022 ;13 904497
    CAR T-Cell Therapy Predictive Response Markers in Diffuse Large B-Cell Lymphoma and Therapeutic Options After CART19 Failure.
    Ana Carolina Caballero, Laura Escribà-Garcia, Carmen Alvarez-Fernández, Javier Briones.
      Immunotherapy with T cells genetically modified with chimeric antigen receptors (CARs) has shown significant clinical efficacy in patients with relapsed/refractory B-cell lymphoma. Nevertheless, more than 50% of treated patients do not benefit from such therapy due to either absence of response or further relapse. Elucidation of clinical and biological features that would predict clinical response to CART19 therapy is of paramount importance and eventually may allow for selection of those patients with greater chances of response. In the last 5 years, significant clinical experience has been obtained in the treatment of diffuse large B-cell lymphoma (DLBCL) patients with CAR19 T cells, and major advances have been made on the understanding of CART19 efficacy mechanisms. In this review, we discuss clinical and tumor features associated with response to CART19 in DLBCL patients as well as the impact of biological features of the infusion CART19 product on the clinical response. Prognosis of DLBCL patients that fail CART19 is poor and therapeutic approaches with new drugs are also discussed.
    Keywords:  CAR-T; DLBCL; antibodies; bispecific; lymphoma
    DOI:  https://doi.org/10.3389/fimmu.2022.904497
  5. J Inflamm Res. 2022 ;15 4061-4085
    From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer.
    Jiangang Sun, Xiaojing Li, Peng Chen, Yongshun Gao.
      Current Therapeutic modalities provide no survival advantage to gastric cancer (GC) patients. Targeting the human epidermal growth factor receptor-2 (HER-2) is a viable therapeutic strategy against advanced HER-2 positive GC. Antibody-drug conjugates, small-molecule tyrosine kinase inhibitors (TKIs), and bispecific antibodies are emerging as novel drug forms that may abrogate the resistance to HER-2-specific drugs and monoclonal antibodies. Chimeric antigen receptor-modified T cells (CAR-T) targeting HER-2 have shown considerable therapeutic potential in GC and other solid tumors. However, due to the high heterogeneity along with the complex tumor microenvironment (TME) of GC that often leads to immune escape, the immunological treatment of GC still faces many challenges. Here, we reviewed and discussed the current progress in the research of anti-HER-2-CAR-T cell immunotherapy against GC.
    Keywords:  CAR-T; HER-2; gastric cancer; immunotherapy; target
    DOI:  https://doi.org/10.2147/JIR.S368138
  6. Mol Cancer Ther. 2022 Jul 25. pii: MCT-22-0059. [Epub ahead of print]
    FGFR4-targeted chimeric antigen receptors (CARs) combined with anti-myeloid poly-pharmacy effectively treats orthotopic rhabdomyosarcoma.
    Peter M Sullivan, Rajesh Kumar, Wei Li, Virginia Hoglund, Lingyang Wang, Yue Zhang, Megan Shi, Dusan Baek, Adam Cheuk, Michael C Jensen, Javed Khan, Dimiter S Dimitrov, Rimas J Orentas.
      Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. Treatment outcomes, particularly for relapsed/refractory or metastatic disease, have not improved in decades. The current lack of novel therapies and low tumor mutational burden suggest that CAR T therapy could be a promising approach to treating RMS. Previous work identified Fibroblast Growth Factor Receptor 4 (FGFR4, CD334) as being specifically upregulated in RMS, making it a candidate target for CAR-T cells. We tested the feasibility of an FGFR4 targeted CAR for treating RMS using an NSG mouse with RH30 orthotopic (intramuscular) tumors. The first barrier we noted was that RMS tumors produce a collagen-rich stroma, replete with immunosuppressive myeloid cells, when T cell therapy is initiated. This stromal response is not seen in tumor-only xenografts. When scFV-based binders were selected from phage display, CARs targeting FGFR4 were not effective until our screening approach was refined to identify binders to the membrane-proximal domain of FGFR4. Having improved the CAR, we devised a pharmacologic strategy to augment CAR-T activity by inhibiting the myeloid component of the T cell-induced tumor stroma. The combined treatment of mice with anti-myeloid polypharmacy (targeting CSF1R, IDO1, iNOS, TGFbeta, PDL1, MIF and myeloid mis-differentiation) allowed FGFR4 CAR-T to successfully clear orthotopic RMS tumors, demonstrating that RMS tumors, even with very low copy number targets, can be targeted by CAR-T upon reversal of an immunosuppressive microenvironment.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-22-0059
  7. Cancer J. 2022 Jul-Aug 01;28(4):28(4): 322-327
    Adoptive Cellular Therapy for Pediatric Solid Tumors: Beyond Chimeric Antigen Receptor-T Cell Therapy.
    Jonathan Hensel, Jonathan Metts, Ajay Gupta, Brian H Ladle, Shari Pilon-Thomas, John Mullinax.
       ABSTRACT: Children and adolescents with high-risk (metastatic and relapsed) solid tumors have poor outcomes despite intensive multimodal therapy, and there is a pressing need for novel therapeutic strategies. Adoptive cellular therapy (ACT) has demonstrated activity in multiple adult cancer types, and opportunity exists to expand the use of this therapy in children. Employment of immunotherapy in the pediatric population has realized only modest overall clinical trial results, with success thus far restricted mainly to antibody-based therapies and chimeric antigen receptor T-cell therapies for lymphoid malignancy. As we improve our understanding of the orchestrated cellular and molecular mechanisms involved in ACT, this will provide biologic insight and improved ACT strategies for pediatric malignancies. This review focuses on ACT strategies outside of chimeric antigen receptor T-cell therapy, including completed and ongoing clinical trials, and highlights promising preclinical data in tumor-infiltrating lymphocytes that enhance the clinical efficacy of ACT for high-risk pediatric solid tumors.
    DOI:  https://doi.org/10.1097/PPO.0000000000000603
  8. J Transl Med. 2022 Jul 28. 20(1): 338
    Identification of genomic determinants contributing to cytokine release in immunotherapies and human diseases.
    Lipei Shao, Alejandra Pelayo, Rongye Shi, Jinxia Ma, Hui Liu, Yihua Cai, Michaela Prochazkova, Robert P Somerville, Sandhya R Panch, Nirali N Shah, David F Stroncek, Ping Jin.
       BACKGROUND: Cytokine release syndrome (CRS) is a strong immune system response that can occur as a result of the reaction of a cellular immunotherapy with malignant cells. While the frequency and management of CRS in CAR T-cell therapy has been well documented, there is emerging interest in pre-emptive treatment to reduce CRS severity and improve overall outcomes. Accordingly, identification of genomic determinants that contribute to cytokine release may lead to the development of targeted therapies to prevent or abrogate the severity of CRS.
    METHODS: Forty three clinical CD22 CAR T-cell products were collected for RNA extraction. 100 ng of mRNA was used for Nanostring assay analysis which is based on the nCounter platform. Several public datasets were used for validation purposes.
    RESULTS: We found the expression of the PFKFB4 gene and glycolytic pathway activity were upregulated in CD22 CAR T-cells given to patients who developed CRS compared to those who did not experience CRS. Moreover, these results were further validated in cohorts with COVID-19, influenza infections and autoimmune diseases, and in tumor tissues. The findings were similar, except that glycolytic pathway activity was not increased in patients with influenza infections and systemic lupus erythematosus (SLE).
    CONCLUSION: Our data strongly suggests that PFKFB4 acts as a driving factor in mediating cytokine release in vivo by regulating glycolytic activity. Our results suggest that it would beneficial to develop drugs targeting PFKFB4 and the glycolytic pathway for the treatment of CRS.
    Keywords:  CAR T-cell therapy; Cytokine release syndrome; Glycolysis; PFKFB4
    DOI:  https://doi.org/10.1186/s12967-022-03531-3
  9. Cancer Discov. 2022 Jul 29. pii: CD-21-1026. [Epub ahead of print]
    Modulation of BCL-2 in both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T cell Immunotherapy against Cancer.
    Yong Gu Lee, Puneeth Guruprasad, Guido Ghilardi, Raymone Pajarillo, Christopher Tor Sauter, Ruchi Patel, Hatcher J Ballard, Seok Jae Hong, Inkook Chun, Nicholas Yang, Kimberly V Amelsberg, Katherine D Cummins, Jakub Svoboda, Saar Gill, Elise A Chong, Khrystyna North, Sarah E Church, Joseph A Fraietta, Wan-Jung Chang, Simon F Lacey, Xueqing Maggie Lu, Yunlin Zhang, Kanupriya Whig, David C Schultz, Sara Cherry, James Gerson, Stephen J Schuster, Patrizia Porazzi, Marco Ruella.
      Chimeric Antigen Receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two-thirds of patients fail this treatment. Resistance to apoptosis is a key feature of cancer cells that associates with treatment failure. In 87 NHL patients treated with anti-CD19 CART, we found that chromosomal alteration of BCL-2, a critical anti-apoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2-inhibitor, venetoclax, and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L) which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells per se enhanced CART anti-tumor activity in preclinical models and in patients by prolonging CART persistence.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1026
  10. Nat Cancer. 2022 Jul;3(7): 790-792
    PARP11 interfer(on)es with CAR T cell efficacy.
    Isabelle Munoz, Paul A Beavis.
      
    DOI:  https://doi.org/10.1038/s43018-022-00406-w
  11. Int Immunol. 2022 Jul 28. pii: dxac038. [Epub ahead of print]
    CD8 T cell heterogeneity during T cell exhaustion and PD-1-targeted immunotherapy.
    Satomi Ando, Koichi Araki.
      Persistent antigenic stimulation results in loss of effector function or physical deletion of antigen-specific CD8 T cells. This T cell state is called T cell exhaustion and occurs during chronic infection and cancer. Antigen-specific CD8 T cells during T cell exhaustion express the inhibitory receptor PD-1, the expression of which plays a major role in T cell dysfunction. PD-1 blockade re-invigorates CD8 T cell immunity and has been proven effective against many different types of human cancer. To further improve the efficacy of PD-1-targeted immunotherapy in cancer patients, a better understanding of T cell exhaustion is required. Recent studies have revealed that antigen-specific CD8 T cells during T cell exhaustion are heterogeneous and have also uncovered the detailed mechanisms for PD-1-targeted immunotherapy. Here, we review the CD8 T cell subsets that arise during T cell exhaustion, the lineage relationship among these individual subsets and the role of each subset in PD-1 blockade. Also, we discuss potential strategies to enhance the efficacy of PD-1-targeted immunotherapy.
    Keywords:  Cancer; Chronic infection; Immune checkpoint inhibitors; LCMV; Stem-like; Terminally exhausted; transitory
    DOI:  https://doi.org/10.1093/intimm/dxac038
  12. Vaccines (Basel). 2022 Jun 28. pii: 1033. [Epub ahead of print]10(7):
    NK Cell-Based Immunotherapy in Colorectal Cancer.
    Mariella Della Chiesa, Chiara Setti, Chiara Giordano, Valentina Obino, Marco Greppi, Silvia Pesce, Emanuela Marcenaro, Mariangela Rutigliani, Nicoletta Provinciali, Laura Paleari, Andrea DeCensi, Simona Sivori, Simona Carlomagno.
      Human Natural Killer (NK) cells are all round players in immunity thanks to their powerful and immediate response against transformed cells and the ability to modulate the subsequent adaptive immune response. The potential of immunotherapies based on NK cell involvement has been initially revealed in the hematological setting but has inspired the design of different immune tools to also be applied against solid tumors, including colorectal cancer (CRC). Indeed, despite cancer prevention screening plans, surgery, and chemotherapy strategies, CRC is one of the most widespread cancers and with the highest mortality rate. Therefore, further efficient and complementary immune-based therapies are in urgent need. In this review, we gathered the most recent advances in NK cell-based immunotherapies aimed at fighting CRC, in particular, the use of monoclonal antibodies targeting tumor-associated antigens (TAAs), immune checkpoint blockade, and adoptive NK cell therapy, including NK cells modified with chimeric antigen receptor (CAR-NK).
    Keywords:  CAR-NK cells; CRC; NK cells; bispecific antibodies; immune checkpoints; immunotherapies; monoclonal antibodies; trispecific engagers
    DOI:  https://doi.org/10.3390/vaccines10071033
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