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Review
. 2020 Jun 1;26(11):2444-2451.
doi: 10.1158/1078-0432.CCR-19-1835. Epub 2020 Feb 3.

Enhancing Chimeric Antigen Receptor T-Cell Efficacy in Solid Tumors

Giovanni Fucà  1   2 , Loic Reppel  3 , Elisa Landoni  3 , Barbara Savoldo  3   4 , Gianpietro Dotti  1   5
Affiliations
Review

Enhancing Chimeric Antigen Receptor T-Cell Efficacy in Solid Tumors

Giovanni Fucà et al. Clin Cancer Res. .

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has been acclaimed as a revolution in cancer treatment following the impressive results in hematologic malignancies. Unfortunately, in patients with solid tumors, objectives responses to CAR T cells are still anecdotal, and important issues are driven by on-target but off-tumor activity of CAR T cells and by the extremely complex biology of solid tumors. Here, we will review the recent attempts to challenge the therapeutic impediments to CAR T-cell therapy in solid tumors. We will focus on the most promising strategies of antigen targeting to improve tumor specificity and address the tumor heterogeneity, efforts to circumvent the physical barriers of the tumor architecture such as subverted tumor vasculature, impediments of CAR T-cell trafficking and immune suppressive microenvironment.

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Conflict of interest statement

Conflict of interest disclosure statement:

Drs Dotti and Savoldo hold patents in the field of T cell engineering and have sponsor research agreements with Bluebird Bio, Cell Medica and Bellicum Pharmaceutical. Dr. Dotti serves in the scientific advisory board of MolMed S.p.A and Bellicum Pharmaceutical. All the other authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. Strategies to overcome physical barriers in solid tumors.
Local T cell delivery can maximize the accumulation of CAR T cells at the tumor site and may also improve the safety profile (panel A). Biomaterials can be used to enhance the persistence and functionality of locally delivered CAR T cells (panel B). CAR T cells can be combined with antiangiogenic drugs in the effort of normalizing the intratumoral blood flow or with immunomodulating agents or engineered with cytokine receptors to enhance the trafficking (panel C).
Figure 2.
Figure 2.. Strategies to counteract the immune suppressive tumor microenvironment.
Neutralization of inhibitory mechanisms can be carried out by either knocking down specific receptors in CAR T cells such as PD1 or Fas, by engineering CAR T cells to express dominant negative receptors (DNRs) and by combining CAR T cells with the systemic administration or transgenic production of immune checkpoint inhibitors (panel A). Other strategy to overcome the immune suppressive tumor microenvironment consist in myeloid-derived suppressor cell (MDSCs) depletion, metabolic reprogramming of CAR T cells and transgenic cytokine production (panel B).
See this image and copyright information in PMC

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