{"id":4308,"date":"2017-03-08T11:05:34","date_gmt":"2017-03-08T16:05:34","guid":{"rendered":"http:\/\/blogs.shu.edu\/cancer\/?p=4308"},"modified":"2021-07-02T08:51:42","modified_gmt":"2021-07-02T12:51:42","slug":"juno-advances-car-t-cell-car017-and-halts-car015-in-non-hodgkin-lymphoma","status":"publish","type":"post","link":"http:\/\/blogs.shu.edu\/cancer\/2017\/03\/08\/juno-advances-car-t-cell-car017-and-halts-car015-in-non-hodgkin-lymphoma\/","title":{"rendered":"Juno Advances CAR T-cell CAR017 and Halts CAR015 in Non-Hodgkin Lymphoma"},"content":{"rendered":"

Juno Therapeutics is developing Chimeric Antigen Receptor (CAR) T-cells<\/a> directed against B-cell antigen CD19 for the treatment of patients with B-cell lymphomas. The company has elected to halt the development of JCAR015 for Acute Lymphoblastic Leukemia (ALL) and proceed with JCAR017 for relapsed\/refractory diffuse large B-cell lymphoma (DLBCL), the most common form of Non-Hodgkin Lymphoma (NHL), due to the development of cerebral edema and subsequent death<\/a> of several patients with ALL enrolled in its phase 2 ROCKET trial<\/a>, which has been suspended.<\/p>\n

Chimeric Antigen Receptor T-cells<\/em><\/strong><\/p>\n

CAR T-cells have evolved<\/a> from first generation constructs that contained an extracellular binding domain and intracellular signaling domain, to third generation structures that also include co-stimulatory molecules.<\/p>\n

<\/a>

http:\/\/www.discoverymedicine.com\/Michael-S-Magee\/2014\/11\/challenges-to-chimeric-antigen-receptor-car-t-cell-therapy-for-cancer\/<\/a><\/p><\/div>\n

CD19<\/em><\/strong><\/p>\n

JCAR015 and JCAR017 both target the CD19 antigen, a 95 kilodalton glycoprotein belonging to the immunoglobulin class. No significant homology<\/a> exists between CD19 and other known proteins, making it an ideal biomarker for B-cells.<\/p>\n

CD19 acts as a critical co-receptor for BCR signal transduction. As BCR (B-cell receptor) signaling requires protein tyrosine kinase (PTK) activation, CD19 recruits and amplifies the activation of Src-family protein tyrosine kinases such as Lyn and Fyn. Upon BCR activation, CD19 also enhances BCR-induced signaling crucial for B cell expansion, through recruitment and activation of PI3K and downstream Akt kinases.<\/em><\/p>\n

<\/a>

Figure 2. CD19 associated signaling complex. Antigen-C3d complexes can engage the CD19\/21 complex in both a BCR-independent or BCR-dependent fashion. The CD19 complex includes complement receptor CD21, which binds C3d-modified antigen. Rituxan (rituximab)<\/a>, a monoclonal antibody for the treatment of Non-Hodgkin\u2019s Lymphoma (DLBCL) and Chronic Lymphocytic Leukemia, binds to CD19.<\/p><\/div>\n

JCAR015 versus JCAR017<\/em><\/strong><\/p>\n

These Chimeric Antigen Receptors are comprised of four domains: (1) extracellular targeting \u2013 single chain variable fragment; (2) transmembrane; (3) cytoplasmic costimulatory; and (4) cytoplasmic signaling domain.<\/p>\n

Upon recognition and binding of the scFv<\/a> of the CAR T cell to the cancer cell, there is a conformational change that leads to an activation signal to the cell through CD3-zeta, an intracellular signaling protein. Our current CAR constructs also include either a CD28 or 4-1BB costimulatory signaling domain to mimic a \u201csecond signal\u201d that amplifies the activation of the CAR T cells, leading to a more robust signal to the T cell to multiply and kill the cancer cell.<\/em><\/p>\n

<\/a>

Figure 3. Template of JCAR015 and JCAR017. https:\/\/www.junotherapeutics.com\/our-science\/car-technology\/<\/a><\/p><\/div>\n

There are important differences between JCAR015 and JCAR017<\/a>, which likely account for the improved safety profile of the latter:<\/p>\n

    \n
  1. The cells used to create JCAR015 are composed of CD3+ enriched peripheral blood mononuclear cells, whereas JCAR017 is built using a fixed ratio of CD4+ and CD8+ T-lymphocytes. <\/em><\/li>\n
  2. Each agent is engineered using different viral vectors, namely gamma retroviral for JCAR015 and lentiviral for JCAR017. <\/em><\/li>\n
  3. The binding domain for JCAR015 is SJ25C1 and the costimulatory domain is CD28, whereas JCAR017 has a binding domain of FMC63 and a costimulatory domain of 4-1BB.<\/em><\/li>\n
  4. JCAR017 contains an ablative technology to provide better control of proliferation and survival of the engineered T cells, which is not included in JCAR015. This ablative technology, a truncated form of the human epidermal growth factor receptor (EGFRt), allows for rapid killing of the CAR T-cells using <\/em>cetuximab (Erbitux)<\/a>, if needed. The addition of EGFRt may also have immunostimulating properties. <\/em><\/li>\n<\/ol>\n

    By including only CD4+ (T-helper) and CD-8+ (Cytotoxic T-cells), the immune attack is more focused \u2013 CD3+ positive cells also include macrophages<\/a>. Co-stimulatory molecule CD28 stimulates the B7 signaling pathway, which results in stabilization of cytokine mRNA, whereas, 4-1BB triggers the tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) pathway, which results activation of NFkB . CAR T-cells with CD28 expand rapidly, whereas, those with 4-1BB expand more slowly \u2013 this is thought to contribute to improved tolerability, including less cerebral edema.<\/p>\n

    <\/a>

    Figure 4. Biochemical and transcriptional effects of the CD28 signaling pathways. Summary of biochemical signaling events downstream of the proximal and distal CD28 motifs that can modulate the T-cell transcription pattern after co-stimulation. Among the different mechanisms, we can distinguish a direct effect on gene expression by regulation of transcription factors or an indirect effect through increases in mRNA stability. https:\/\/www.researchgate.net\/figure\/51047463_fig3_Figure-1-Biochemical-and-transcriptional-effects-of-the-CD28-signaling-pathways-Summary<\/a><\/p><\/div>\n

    CAR T-cells incorporating 4-1BB are more persistent and less likely to undergo exhaustion<\/a> than those incorporating CD28. This probably contributes to improved effectiveness seen with CAR017. Inclusion of EGFR in the construct adds a great measure of safety \u2013 the ability to neutralize the CAR T-cells is critical should adverse events emerge.<\/p>\n

    <\/a>

    Figure 5. 4-1BB signaling. http:\/\/rgcb.res.in\/orcadb\/biocarta_analysis.php?gene_id=7018&gene_symbol=TF<\/a><\/p><\/div>\n

    Clinical results with JCAR017<\/em><\/strong><\/p>\n

    JCAR017 has shown impressive results in the clinic to data<\/a>. In a phase 1 study in patients with NHL, a 60% complete response (CR) rate and an 80% overall response rate were observed. None of the patients experienced severe cytokine release syndrome (CRS) and fourteen percent experienced neurotoxicity, which resolved with treatment.<\/p>\n

    In a phase 1 study of young patients with relapsed\/refractory CD-19 positive ALL, the minimal residual disease (MRD)<\/a>-negative CR rate was 93%. In those pre-treated with fludarabine and cyclophosphamide, the MRD-negative CR rate was 100%. Twenty-three percent experienced severe CRS, and grade 3 neurotoxicity was seen in 23% of patients.<\/p>\n

    In adults with ALL, the CR rate was 77% and the MRD-negative rate was 90% (in those who could be evaluated for MRD). Twenty-seven percent of patients experienced severe CRS, and twenty-nine percent had grade 3 or 4 neurotoxicity.<\/p>\n

     <\/p>\n","protected":false},"excerpt":{"rendered":"

    Juno Therapeutics is developing Chimeric Antigen Receptor (CAR) T-cells directed against B-cell antigen CD19 for the treatment of patients with B-cell lymphomas. The company has elected to halt the development of JCAR015 for Acute Lymphoblastic Leukemia (ALL) and proceed with JCAR017 for relapsed\/refractory diffuse large B-cell lymphoma (DLBCL), the most common form of Non-Hodgkin Lymphoma […]<\/p>\n","protected":false},"author":2252,"featured_media":3979,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[30,6,712,1],"tags":[233,554,182,1762,1883,1122,1881,1877,1878,1885,1879,1880,1882,806,1876,1884],"class_list":["post-4308","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-car-t","category-immunology-immunotherapy","category-passive-immunotherapy","category-uncategorized","tag-4-1bb","tag-acute-lymphoblastic-leukemia","tag-all","tag-car-t-cell","tag-cd-19","tag-cd28","tag-chimeric-antigen-receptor","tag-diffuse-large-b-cell-lymphoma","tag-dlbcl","tag-fmc63","tag-jcar015","tag-jcar017","tag-juno-therapeutics","tag-nhl","tag-non-hodgkin-lymphoma","tag-sj25c1"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4308","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/users\/2252"}],"replies":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/comments?post=4308"}],"version-history":[{"count":4,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4308\/revisions"}],"predecessor-version":[{"id":4873,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4308\/revisions\/4873"}],"wp:featuredmedia":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media\/3979"}],"wp:attachment":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media?parent=4308"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/categories?post=4308"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/tags?post=4308"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}