key: cord-0927728-dqs450vq authors: Yilmaz, Ahmet; Yu, Jianhua title: Effects of the COVID-19 pandemic on publication landscape in chimeric antigen receptor-modified immune cell research date: 2021-06-02 journal: bioRxiv DOI: 10.1101/2021.06.01.446639 sha: c8ea22209e7f983f42c9e766627efd95c35d71e4 doc_id: 927728 cord_uid: dqs450vq Chimeric antigen receptors (CARs) are artificial receptors introduced mainly into T cells. CAR-induced immune cell (CARi) products have achieved impressive success rates in treating some difficult-to-treat hematological malignancies. Here, we describe effects of the global COVID-19 pandemic on CARi publication landscape. Due to the pandemic, the total number of publications decreased in 2020 compared to 2019 in all fields of cancer immunotherapy except CARi. Nearly exponential increases in the number of CARi publications slowed-down in 2020 for the first time in the past 11 years. There were more CARi than coronavirus publications until 2020 when coronavirus publications increased over 5,000% compared to 2019 (575 publications in 2019 vs. 30,390 in 2020). Unlike cancer immunotherapy where the majority of the publications consist of conference abstracts and review articles, majority of the coronavirus publications are original research articles. There are more coronavirus publications in Pubmed than Embase. The opposite is true for CARi publications. Our analysis of the data from the FDA Adverse Event Reporting System (FAERS) show significantly higher death rate in patients treated with Kymirah than Yescarta (28.14% vs. 16.02%). Kymirah and Yescarta are the two main CAR T cell products for treatment of DLBCL and/or B-ALL. However, despite being highly significant, this result is not easily interpretable due to multiple confounding variables in the FAERS data. Our analysis additionally suggest that the significant effects of co-stimulatory domains (4-1BB vs. CD28) consistently reported in preclinical studies do not translate into clinical results. Our manual curation of the CARi publications in PubMed shows that only 5.2% of the publications report results from CARi clinical trials, although we found 663 clinical trials listed on ClinicalTrials.gov database. In conclusion, publication landscape in CARi as well as other fields of cancer immunotherapy has changed due to the global COVID-19 pandemic. This trend will likely continue in the near future. CARi research is now in need of increased measures by publishers to reduce repetitive and/or duplicate publications and more stringent criteria for data entry into public databases including PubMed, Embase, ClinicalTrials.gov, and FAERS to advance this important field of medical research. CARi research has been one of the most exciting fields in immunotherapy. Anti-CD19 CAR T cells have achieved unprecedented success rates as high as 90% in treating relapsed or refractory acute lymphoblastic leukemia (ALL) and other B cell leukemia and lymphomas, bringing fresh hope to cancer patients and prompting the FDA to issue breakthrough designations 7 . CARi therapy is one of the costliest types of immunotherapy, but it is covered by The Centers for Medicare and Medicaid Services in the U.S. The CARi technology is projected to create a market in the range of billions of U.S. dollars in the near future 8 Fig. 1H ), the latter institutions published 2.2-fold (772 vs. 348) more total manuscripts including 2.4-fold (220 vs. 92) more review articles than their Chinese counterparts as revealed by searching the terms "Zhejiang", "Beijing", "Hebei", "Pennsylvania", "City of Hope", or "National Institutes of Health" in PubMed along with the terms "chimeric antigen receptor". Interestingly, Zhejiang University Hospitals, a Chinese institution conducting the largest number of clinical trials, conducted more trials (30 vs Safety of CAR T cell products is investigated in 12.5% of the sampled publications in PubMed. The four CAR T cell products already approved by the U.S. FDA include Kymirah (tisagenlecleucel) by Novartis, Breyanzi (lisocabtagene maraleucel) by Juno Therapeutics (now a part of Celgene), and Yescarta (axicabtagene ciloleucel) and Tecartus (brexucabtagene autoleucel) by Kite Pharma (now a part of Gilead Sciences) (Supp. with Breyanzi, all 50 events occurred before the approval of Breyanzi by the FDA in February 2021. Therefore, they may not be considered as "post-marketing" events. Although limited by multiple confounding variables, the higher death rate reported in patients with AEs treated with Kymirah (28%) than Yescarta (16.02%) and Breyanzi (18%) is still intriguing. Disease type could be important in these differences because Yescarta and Breyanzi are only indicated for DLBCL, whereas Kymirah is indicated for both DLBCL and B-ALL. An interesting observation can be made regarding the role of co-stimulatory domains in these death rates. Preclinical studies have consistently shown that 4-1BB is safer than CD28 9 . However, the death rate is higher in Kymirah, which contains 4-1BB, than Yescarta, which contains CD28. In addition, death rates in Breyanzi and Yescarta, which have different co-stimulatory domains but indicated for the same disease, are similar. These observations suggest that the significant effects of costimulatory domains reported in preclinical studies do not necessarily translate into real-world scenarios. These data from FAERS, an official database, are difficult to interpret due to many confounding variables. Reporting AEs to FAERS is currently voluntary. Therefore, some severe AEs may not have been reported. It is unknown how many patients were treated successfully and, thus, were not reported. Additionally, the number of AEs in patients treated with CARi products in FAERS has an unusually wide range (1 to 35) , suggesting that some institutions may have entered only the partial AE profile of patients. Several variables such as event date, age, or weight have been entered for some patients but not for others. It is not clear whether FDA has any oversight at all on data entry. In addition, these drugs are administered to different patient populations, likely following different protocols. Considering that the patients are heavily pre-treated before starting the CAR T therapy, most patients likely suffer from multiple conditions. It is not clear if or how many of these AEs are due to secondary conditions, or other drugs used to treat them, rather than the CAR T therapy itself. All of the anti-CD19 CAR T products including Kymirah, Yescarta, Tecartus, and Breyanzi were granted "fast-track" approval by the FDA based on the JULIET (Phase II), ZUMA-1 (Phase I/II), ZUMA-2 (Phase II), and TRANSCEND-NHL-001 (Phase I) clinical trials, respectively. We are not aware of any Phase III clinical trials reported to evaluate these products. Well-controlled, randomized clinical trials are needed to assess the efficacy and safety profiles of these CARmodified T cell products. Until then, the pivotal trials that led to the FDA approval, and were recently reviewed by us 10 suggesting that these 26 publications were likely entered twice in databases used to obtain the "results by year" timeline although it is unknown why the search produced 151 rather than 156 publications. We included only data obtained through the "search" function of the PubMed in this manuscript as the "results by year" timeline does not seem reliable. In conclusion, publication landscape in CARi as well as other fields of cancer immunotherapy has changed due to the global COVID-19 pandemic. This trend will likely continue in the near future as scientists try to contain the pandemic. CARi research is now in need of increased measures by publishers to reduce non-peer-reviewed, repetitive and/or duplicate publications, at least in highimpact journals, and more stringent criteria for data entry into public databases including PubMed, Embase, ClinicalTrials.gov, and FAERS. These measures have the potential to significantly ease the burden on scientists trying to obtain reliable data that they urgently need to advance this important field of medical research. All A B C D Figure 5 . Total cancer immunotherapy and coronavirus publications from 1989 to 2020 in PubMed vs. Embase. PubMed contains fewer total but more review articles than Embase in all cancer immunotherapy fields. In coronavirus research, however, there are more both overall and review manuscripts in PubMed than Embase. All = all publication types including original research articles, reviews, conference abstracts, etc; reviews = review manuscripts; CARi = chimeric antigen receptor-modified immune cells; ADC = antibody drug conjugate. The first FDA-approved gene therapy 140 (along with Luxturna) The first FDA-approved CAR-T cell product for large B cell lymphoma 139 The first cell-based therapy for MCL, an aggressive type of B cell non-Hodgkin's lymphoma seen mostly in adults over 60 years of age with no proven therapy regimen 141 The first CAR T cell therapy with the regenerative medicine advanced therapy designation Death rate b 435 (28.14%) 332 (16.02%) 1 (50%) 9 (18%) a r/r = relapsed/refractory; nos = not otherwise specified; MCL = mantle cell lymphoma, AE = adverse event. b Death rate as a percentage of serious adverse events. The IL-15-AKT-XBP1s signaling pathway contributes to effector functions and survival in human NK cells NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors Innate or adaptive immunity? The example of natural killer cells Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells Inflammatory and Infectious Syndromes Associated With Cancer Immunotherapies Cryo-EM structure of the B cell co-receptor CD19 bound to the tetraspanin CD81 B-cell maturation antigen expression across hematologic cancers: a systematic literature review Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus Mesothelin-targeted CAR-T cell therapy for solid tumors Coordinated roles for glycans in regulating the inhibitory function of CD22 on B cells Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study Simultaneous engagement of FcgammaIIb and CD22 inhibitory receptors silences targeted B cells and suppresses autoimmune disease activity CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy Targeting B Cells and Plasma Cells in Autoimmune Diseases CD20 deficiency in humans results in impaired T cell-independent antibody responses Generation and characterization of a mouse single-chain antibody fragment specific for disialoganglioside (GD2) HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry A Real-world Perspective of CD123 Expression in Acute Leukemia as Promising Biomarker to Predict Treatment Outcome in B-ALL and AML glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development Triple-negative and HER2-positive breast cancers found by mammography screening show excellent prognosis Small molecule inhibitors targeting the EGFR/ErbB family of proteintyrosine kinases in human cancers Modulating MUC1 Function on T Cells Biomarkers for evaluation of prostate cancer prognosis Prostate-specific membrane antigen (PSMA) enzyme activity is elevated in prostate cancer cells Relapsed T Cell ALL: Current Approaches and New Directions Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking CEA adhesion molecules: multifunctional proteins with signal-regulatory properties New drugs creating new challenges in acute myeloid leukemia Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years? Functions of NKG2D in CD8(+) T cells: an opportunity for immunotherapy B7-H3 role in the immune landscape of cancer B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer Expression of olfactomedin 4 and claudin-18 in serrated neoplasia of the colorectum: a characteristic pattern is associated with sessile serrated lesion Expression of ROR1 has prognostic significance in triple negative breast cancer Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development High expression of ROR2 in cancer cell correlates with unfavorable prognosis in colorectal cancer TGF-beta upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma Robust isolation of malignant plasma cells in multiple myeloma Evidence that IL-13R alpha2 chain in human glioma cells is responsible for the antitumor activity mediated by receptor-directed cytotoxin therapy The Lewis-Y carbohydrate antigen is expressed by many human tumors and can serve as a target for genetically redirected T cells despite the presence of soluble antigen in serum New prospects on the NKG2D/NKG2DL system for oncology Molecular functions of syndecan-1 in disease CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells L1CAM: Cell adhesion and more Clinical immunotherapy of B-cell malignancy using CD19-targeted CAR Tcells BiRd (clarithromycin, lenalidomide, dexamethasone): an update on longterm lenalidomide therapy in previously untreated patients with multiple myeloma New Insights in Anti-Angiogenesis in Multiple Myeloma Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance The PD-1 pathway in tolerance and autoimmunity PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome Targeting CLL-1 for acute myeloid leukemia therapy Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by downregulating the cyclin-dependent kinase inhibitor p27(kip1) Interleukin-7 permits Th1/Tc1 maturation and promotes ex vivo expansion of cord blood T cells: a critical step toward adoptive immunotherapy after cord blood transplantation The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment PGE(2) transiently enhances DC expression of CCR7 but inhibits the ability of DCs to produce CCL19 and attract naive T cells IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice The potential and promise of IL-15 in immunooncogenic therapies The central role of initiator caspase-9 in apoptosis signal transduction and the regulation of its activation and activity on the apoptosome IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile Increased CCR4 expression in cutaneous T cell lymphoma Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4 Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma CXCR5 identifies a subset of Vgamma9Vdelta2 T cells which secrete IL-4 and IL-10 and help B cells for antibody production Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells IL-12 produced by dendritic cells augments CD8+ T cell activation through the production of the chemokines CCL1 and CCL17 Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12 Interleukin-7: a new hematopoietic growth factor B7-H3 Immune Checkpoint Protein in Human Cancer Murine B7-H3 is a negative regulator of T cells IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells Interleukin-21 induces T-cell activation and proinflammatory cytokine secretion in rheumatoid arthritis Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells IL-21 is required to control chronic viral infection T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors Viral Delivery of CAR Targets to Solid Tumors Enables Effective Cell Therapy T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptortransduced T Cells Targeting EGFRvIII in Patients With Glioblastoma Expression of chimeric antigen receptors in natural killer cells with a regulatory-compliant non-viral method Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies Anti-CD20 chimeric antigen receptor (CAR) modified expanded natural killer (NK) cells significantly mediate rituximab sensitive and resistant burkitt lymphoma (BL) regression and improve survival in human BL xenografted NSG mice Retargeting NK-92 cells by means of CD19-and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma Retargeting NK-92 for anti-melanoma activity by a TCR-like singledomain antibody NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells ErbB2/HER2-Specific NK Cells for Targeted Therapy of Glioblastoma Modification of Natural Killer cells to target tumors 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumorspecific antigen receptor A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy F-FDG-PET/CT and diffusion-weighted MRI for monitoring a BRAF and CDK 4/6 inhibitor combination therapy in a murine model of human melanoma. Cancer imaging : the official publication of the International Cancer Imaging Society Anti-αFR CAR-engineered NK-92 Cells Display Potent Cytotoxicity Against αFR-positive Ovarian Cancer Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer Dual targeting of glioblastoma with chimeric antigen receptorengineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer Targeting Ewing sarcoma with activated and GD2-specific chimeric antigen receptor-engineered human NK cells induces upregulation of immuneinhibitory HLA-G. Oncoimmunology 6, e1250050 HAVE PDF Improved Killing of Ovarian Cancer Stem Cells by Combining a Novel Chimeric Antigen Receptor-Based Immunotherapy and Chemotherapy Characterization of a Novel Third-Generation Anti-CD24-CAR against Ovarian Cancer Development of c-MET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells Specific growth inhibition of ErbB2-expressing human breast cancer cells by genetically modified NK-92 cells Engineering NK Cells Modified With an EGFRvIII-specific Chimeric Antigen Receptor to Overexpress CXCR4 Improves Immunotherapy of CXCL12/SDF-1α-secreting Glioblastoma High Cytotoxic Efficiency of Lentivirally and Alpharetrovirally Engineered CD19-Specific Chimeric Antigen Receptor Natural Killer Cells Against Acute Lymphoblastic Leukemia Novel Human NK Cell Line Carrying CAR Targeting EGFRvIII Induces Antitumor Effects in Glioblastoma Cells Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth Efficient generation of gene-modified human natural killer cells via alpharetroviral vectors Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells Development of GPC3-Specific Chimeric Antigen Receptor-Engineered Natural Killer Cells for the Treatment of Hepatocellular Carcinoma ErbB2/HER2-Specific NK Cells for Targeted Therapy of Glioblastoma Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models Eligibility of patients for CAR T-cell: Expert opinion-based collaborative work by the SFGM-TC Current Progress in CAR-T Cell Therapy for Hematological Malignancies Tisagenlecleucel for B-Cell Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma -Project Protocol, Clinical Section (Canadian Agency for Drugs and Technologies in Health Challenges and strategies of clinical application of CAR-T therapy in the treatment of tumors-a narrative review FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma Advances in chimeric antigen receptor T cells The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19 Risk -adapted intensive induction therapy, autologous stem cell transplantation, and rituximab maintenance allow to reach a high 7-year survival rate in patients with mantle cell lymphoma Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL Industry's Giant Leap Into Cellular Therapy: Catalyzing Chimeric Antigen Receptor T Cell (CAR-T) Immunotherapy Value and affordability of CAR T-cell therapy in the United States KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma Anti-CD19 Chimeric Antigen Receptor T Cell Therapies: Harnessing the Power of the Immune System to Fight Diffuse Large B Cell Lymphoma CAR-T TREK through the lymphoma universe, to boldly go where no other therapy has gone before The authors regret that it was not possible to include many interesting studies in the field due to limited space. All authors wrote the initial draft, revised the review, finalized the last version of the article, and approved the final version. Dr. Jianhua Yu is the co-founder of the Cytoimmune, Inc.