Chimeric Antigen Receptors in Cancer Immuno-Gene Therapy: Current Status and Future Directions

Figures & data

FIGURE 1  Chimeric antigen receptor. Schematic representation of the standard structure of a chimeric antigen receptor. V_H, heavy-chain variable domain; V_L, light-chain variable domain; scFv, single chain fragment variable.

TABLE 1  Published clinical trials

Target Antigen	Disease	CAR	Reference
gp100	AIDS	CD4-zeta	Mitsuyasu, 2000 [61]
CD20	Follicular lymphoma	scFv-zeta	Wang, 2004 [62]
G250	Renal cell carcinoma	scFv-gamma	Lamers, 2006 [7]
Folate receptor	Ovarian cancer	scFv-zeta	Kershaw, 2006 [64]
CD171	Neuroblastoma	scFv-zeta	Park, 2007 [63]
CD20	non-Hodgkin lymphoma/mantle	scFv-zeta	Till, 2008 [8]
	cell lymphoma
GD2	Neuroblastoma	scFv-zeta	Pule, 2008 [9]

Clinical trials published until June 2011 using CARs for the treatment of diseases. The completed clinical trials published so far used only first-generation CARs. Ongoing trials with case reports of partial data were not included and can be seen throughout the review and at (www.clinicaltrials. gov or www.wiley.com/legacy/wileychi/genmed/clinical).

FIGURE 2  Strategies to circumvent off-target effects. The off-target effects can be minimized through (a) a suicide gene system to delete remaining cells that recognize the target antigen; (b) splitting the activation endodomains (signal 1 and signal 2) in two different CARs to enable a complete activation response only after interaction of both CARs with their target antigens at the tumor surface. A similar approach was published by Duong et al. and consisted of using two different CARs to promote more potent responses against target cells expressing two tumor antigens [89]; (c) the use of inhibitory CARs, besides an activating receptor, to impair T-cell activation after interaction with the target antigen at the normal tissues; (d) fine tuning of CAR affinity based on the target antigen level of expression. In an ideal situation, it is possible that a lower affinity would lead to recognition of tumor cells expressing high levels of antigen, sparing normal cells with low expression of the same antigen.

Chan CH, Stanners CP. Novel mouse model for carcinoembryonic antigen-based therapy. Mol Ther. 2004;9(6):775–785.

 PubMed Web of Science ®Google Scholar

Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010;116(19):3875–3886.

 PubMed Web of Science ®Google Scholar

Lamers CH, Sleijfer S, Vulto AG, Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol. 2006;24(13):e20–e22.

 PubMedGoogle Scholar

Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7(2):118–130.

 PubMed Web of Science ®Google Scholar

Cheadle EJ, Hawkins RE, Batha H, O'Neill AL, Dovedi SJ, Gilham DE. Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. J Immunol. 2010;184(4):1885–1896.

 PubMed Web of Science ®Google Scholar

Till BG, Jensen MC, Wang J, Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008;112(6):2261–2271.

 PubMed Web of Science ®Google Scholar

Pule MA, Savoldo B, Myers GD, Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14(11):1264–1270.

 PubMed Web of Science ®Google Scholar

Duong CP, Westwood JA, Berry LJ, Darcy PK, Kershaw MH. Enhancing the specificity of T-cell cultures for adoptive immunotherapy of cancer. Immunotherapy. 2011;3(1):33–48.

 Google Scholar