Approaches for refining and furthering the development of CAR-based T cell therapies for solid malignancies.

Published on May 26, 2021in Expert Opinion on Drug Discovery4.887
· DOI :10.1080/17460441.2021.1929920
Caroline M Hull (Guy's Hospital), John Maher33
Estimated H-index: 33
('KCL': King's College London)
Introduction: Chimeric antigen receptor-engineered T-cells typically use the binding domains of antibodies to target cytotoxicity toward tumors. This approach has produced great efficacy against selected hematological cancers, but benefit in solid tumors has been limited. Characteristically, the microenvironment in solid tumors restricts CAR T cell function, thereby limiting success. Enhancing efficacy will depend on novel target discovery to refine specificity and reduce toxicity. Additionally, overcoming immunosuppressive mechanisms may be achieved by altering the structure of the CAR itself, together with ancillary gene expression or additional therapeutic interventions.Areas covered: Herein, the authors discuss approaches for refining and further developing CAR T cell therapies specifically for use with solid malignancies. The authors survey the existing literature and provide perspectives for the future.Expert opinion: Pronounced efficacy in solid tumors will likely require combination therapies, targeting both the tumor itself and associated immunosuppressive mechanisms. Future exploration of CAR T cell therapies for solid tumors is likely to incorporate next-generation designs that couple more precise targeting of cancer-associated targets with enhanced potency and resistance to exhaustion.
📖 Papers frequently viewed together
8 Citations
32 Citations
#1Yu-Yang Ng (NUS: National University of Singapore)H-Index: 1
#2Johan Chin-Kang Tay (NUS: National University of Singapore)H-Index: 6
Last. Shu Wang (NUS: National University of Singapore)H-Index: 59
view all 6 authors...
Cytokine-related toxicity associated with the use of highly active chimeric antigen receptor T cells (CAR-T cells) is a significant clinical problem. By fusing the natural killer group 2D (NKG2D) ectodomain to 4-1BB and the DAP12 cytoplasmic domain containing only one immunoreceptor tyrosine-based activation motif, we have developed a 2nd-generation (2nd-Gen) NKG2D CAR for stable expression in human T cells. When compared to T cells modified with NKG2D CAR containing the commonly used CD3ζ activ...
3 CitationsSource
#1Feiyan Mo (BCM: Baylor College of Medicine)H-Index: 3
#2Norihiro Watanabe (Center for Cell and Gene Therapy)H-Index: 8
Last. Maksim MamonkinH-Index: 15
view all 14 authors...
Engineered T cells are effective therapies against a range of malignancies, but current approaches rely on autologous T cells, which are difficult and expensive to manufacture. Efforts to develop potent allogeneic T cells that are not rejected by the recipient’s immune system require abrogating both T- and natural killer (NK)-cell responses, which eliminate foreign cells through various mechanisms. In the present study, we engineered a receptor that mediates deletion of activated host T and NK c...
14 CitationsSource
#1Brooke L. Prinzing (St. Jude Children's Research Hospital)H-Index: 4
#2Patrick SchreinerH-Index: 1
Last. Stephen Gottschalk (St. Jude Children's Research Hospital)H-Index: 55
view all 6 authors...
Chimeric antigen receptor (CAR) T cell therapy for solid tumors has shown limited efficacy in early-phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains, and we explored whether MyD88 and CD40 (MC) costimulatory endodomains in CARs could improve their antitumor activity. We generated CD28-, 41BB-, and MC-CAR T cells and demonstrated that MC-CAR T cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor mo...
1 CitationsSource
#1Iosifina P. Foskolou (University of Cambridge)H-Index: 1
#1Iosifina P. Foskolou (University of Cambridge)H-Index: 6
Last. Randall S. Johnson (University of Cambridge)H-Index: 120
view all 13 authors...
Cancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy is that the ex vivo-generated CAR-T cells become exhausted during expansion in culture, and do not persist when transferred back to patients. It has become clear that naive and memory CD8 T cells perform better than the total CD8 T-cell populations in CAR-T immunotherapy because of better expansion, antitumor activity, and per...
3 CitationsSource
#1Shiwani Agarwal (Paul Ehrlich Institute)H-Index: 3
#2Julia D.S. Hanauer (Paul Ehrlich Institute)H-Index: 2
Last. Christian J. Buchholz (Goethe University Frankfurt)H-Index: 3
view all 6 authors...
Abstract T cells modified with CD19-specific chimeric antigen receptors (CARs) result in significant clinical benefit for leukemia patients but constitute a challenge for manufacturing. We have recently demonstrated the in vivo generation of CD19-CAR T cells using the CD8-targeted lentiviral vector CD8-LV. Here we investigated the in vivo generation of CD4-positive CAR T cells using CD4-targeted LV (CD4-LV). Administration of CD4-LV into NSG mice transplanted with human PBMC led to 40 - 60% of h...
10 CitationsSource
#1Jana Obajdin ('KCL': King's College London)H-Index: 3
#1J. Obajdin ('KCL': King's College London)H-Index: 1
Last. John MaherH-Index: 33
view all 3 authors...
Natural killer (NK) cells are innate immune effectors which play a crucial role in recognising and eliminating virally infected and cancerous cells. They effectively distinguish between healthy and distressed self through the integration of signals delivered by germline-encoded activating and inhibitory cell surface receptors. The frequent upregulation of stress markers on genetically unstable cancer cells has prompted the development of novel immunotherapies that exploit such innate receptors. ...
2 CitationsSource
#1Meir Rozenbaum (TAU: Tel Aviv University)H-Index: 2
#2Amilia Meir (Sheba Medical Center)H-Index: 6
Last. Michal J. Besser (TAU: Tel Aviv University)H-Index: 28
view all 8 authors...
Autologous T cells engineered to express a chimeric antigen receptor (CAR) against the CD19 antigen are in the frontline of contemporary hemato-oncology therapies, leading to high remission rates in B-cell malignancies. Although effective, major obstacles involve the complex and costly individualized manufacturing process, and CD19 target antigen loss or modulation leading to resistant and relapse following CAR therapy. A potential solution for these limitations is the use of donor-derived γδT c...
13 CitationsSource
#1Silvia ArcangeliH-Index: 5
#2Laura FalconeH-Index: 6
Last. Monica CasucciH-Index: 13
view all 10 authors...
Chimeric antigen receptor (CAR) T cell expansion and persistence emerged as key efficacy determinants in cancer patients. These features are typical of early-memory T cells, which can be enriched with specific manufacturing procedures, providing signal one and signal two in the proper steric conformation and in the presence of homeostatic cytokines. In this project, we exploited our expertise with paramagnetic beads and IL-7/IL-15 to develop an optimized protocol for CAR T cell production based ...
7 CitationsSource
#1Sonia Guedan (UPenn: University of Pennsylvania)H-Index: 19
#2Aviv Madar (Novartis)H-Index: 12
Last. Avery D. Posey (UPenn: University of Pennsylvania)H-Index: 22
view all 9 authors...
Chimeric antigen receptor (CAR) T cell therapies can eliminate relapsed and refractory tumors, but the durability of anti-tumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, as well as influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid resi...
28 CitationsSource
#1Xiaomei WangH-Index: 2
#2Daniel L. JasinskiH-Index: 12
Last. J. Henri BayleH-Index: 4
view all 6 authors...
Natural killer (NK) cells expressing chimeric antigen receptors (CARs) are a promising anticancer immunotherapy, leveraging both innate NK cell antitumor activity and target-specific cytotoxicity. Inducible MyD88/CD40 (iMC) is a potent, rimiducid-regulated protein switch that has been deployed previously as a T-cell activator to enhance proliferation and persistence of CAR-modified T cells. In this study, iMC was extended to CAR-NK cells to enhance their growth and augment cytotoxicity against t...
12 CitationsSource
Cited By0