Going viral: chimeric antigen receptor T‐cell therapy for hematological malignancies

Abstract

On July 1, 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to CTL019, the anti-CD19 chimeric antigen receptor T-cell therapy developed at the University of Pennsylvania. This is the first personalized cellular therapy for cancer to be so designated and occurred 25 years after the first publication describing genetic redirection of T cells to a surface antigen of choice. The peer-reviewed literature currently contains the outcomes of more than 100 patients treated on clinical trials of anti-CD19 redirected T cells, and preliminary results on many more patients have been presented. At last count almost 30 clinical trials targeting CD19 were actively recruiting patients in North America, Europe, and Asia. Patients with high-risk B-cell malignancies therefore represent the first beneficiaries of an exciting and potent new treatment modality that harnesses the power of the immune system as never before. A handful of trials are targeting non-CD19 hematological and solid malignancies and represent the vanguard of enormous preclinical efforts to develop CAR T-cell therapy beyond B-cell malignancies. In this review, we explain the concept of chimeric antigen receptor gene-modified T cells, describe the extant results in hematologic malignancies, and share our outlook on where this modality is likely to head in the near future.

Targeting TGF-β Signaling for Therapeutic Gain

“…It is likely that TGF-b inhibitors will have their most important therapeutic activity in cancer through effects on the TME, particularly, but not only, in neutralizing or reversing immune suppression. Indeed, the combination of TGF-b inhibition together with existing immunotherapies, such as cancer vaccines (Jia et al 2005;Nemunaitis and Murray 2006;Kim et al 2008), adoptive Tcell transfer Wallace et al 2008), chimeric antigen receptor T-cell therapy (Gill and June 2015;Wu et al 2015), and immune checkpoint blockade (Topalian et al 2012;Lipson et al 2013), will likely provide the major basis of their therapeutic usage. Here again, the major players appear to be TGF-b1 and -b2.…”

Immune Cells As Targets and Tools For Cancer Therapy

“…Second and third generation of CARs contain not only the main ζ domain of TCR, but also one or more costimulatory domains of CD28, ICOS, or 41BB which provide complete activation signals for T cells. Such CAR T cells are not only more effective in antigen recognition but also in stimulation of proliferation, survival and resistance to T cell anergy [13] (Gill and June, 2015).…”

Engineering opportunities in cancer immunotherapy

“…When the domain recognized is specific to a particular cell type from which cancer cells derive, then the therapy can kill both cancer and normal cells. Such is the case with CAR T-cell therapies targeting CD19 in acute lymphoblastic leukemia, a receptor that is present on both leukemic cells and normal B cells (49,50). Ongoing advances in designing CARs include modifications in their extracellular domain to recognize tumor cells and in their cytoplasmic domain to enhance both efficacy through potent signaling and safety through inclusion of regulatory domains (50).…”