A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-cell Stemness Shows Enhanced CAR T-cell Efficacy in Preclinical and Early Clinical Development

Dickinson, Michael; Barba, Pere; Jaeger, Ulrich; Shah, Nirav N.; Blaise, Didier; Briones, Javier; Shune, Leyla; Boissel, Nicolas; Bondanza, Attilio; Mariconti, Luisa; Marchal, Anne-Laure; Quinn, David S.; Yang, Jennifer; Price, Andrew; Sohoni, Akash; Treanor, Louise M.; Orlando, Elena; Mataraza, Jennifer; Davis, Jaclyn; Lu, Darlene; Zhu, Xu; Engels, Boris; Parseval, Laure Moutouh–de; Brogdon, Jennifer L.; Moschetta, Michele; Flinn, Ian W.

doi:10.1158/2159-8290.cd-22-1276

Cited by 23 publications

(10 citation statements)

References 33 publications

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“…Second, there are no established protocols for consistently generating proliferative memory cells in culture. Although, shorter duration cultures with supportive cytokine cocktails seems to at least preserve memory cell function, improving clinical expansion, persistence, and activity 57 , 58 . Ultimately, the definition of product-intrinsic vs. patient-intrinsic is somewhat circular for autologous cell therapies.…”

Section: Resultsmentioning

confidence: 99%

Making drugs from T cells: The quantitative pharmacology of engineered T cell therapeutics

Kirouac,

Zmurchok,

Morris

2024

npj Syst Biol Appl

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Engineered T cells have emerged as highly effective treatments for hematological cancers. Hundreds of clinical programs are underway in efforts to expand the efficacy, safety, and applications of this immuno-therapeutic modality. A primary challenge in developing these “living drugs” is the complexity of their pharmacology, as the drug product proliferates, differentiates, traffics between tissues, and evolves through interactions with patient immune systems. Using publicly available clinical data from Chimeric Antigen Receptor (CAR) T cells, we demonstrate how mathematical models can be used to quantify the relationships between product characteristics, patient physiology, pharmacokinetics and clinical outcomes. As scientists work to develop next-generation cell therapy products, mathematical models will be integral for contextualizing data and facilitating the translation of product designs to clinical strategy.

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Section: Resultsmentioning

confidence: 99%

Making drugs from T cells: The quantitative pharmacology of engineered T cell therapeutics

Kirouac,

Zmurchok,

Morris

2024

npj Syst Biol Appl

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“… 9 Strategies in autologous CAR-T cell manufacturing to preserve T SCM have been explored showing higher expansion when a preserved T cell phenotype is infused in both animal and human studies. 43 Moreover, translational studies have demonstrated a correlation between higher frequency of T N and T SCM (CD45RO − CD27 + CD8 + T cells) in autologous BCMA-targeted CAR-T and improved patient responses. 17 In the current study, following CAR-T expansion, P-T CD19 CAR-T maintained higher CD27 expression and resisted expression of T EM associated transcription factors when compared with PBMC-CD19 CAR-T.…”

Section: Discussionmentioning

confidence: 99%

“… 17 Another study using patient’s cells in an autologous setting showed that a reduction in culture time during manufacturing enriched for the T SCM population from 17% to 45%. 43 P-T CD19 CAR-T cells have on average >45% T SCM at the end of 13 days manufacturing allowing high CAR-T yield while maintaining stemness. Transcriptome analysis of CAR-T drug products has proven to be a strong predictor of clinical outcome linking the enrichment of non-exhausted memory cell gene signatures with complete remission.…”

Section: Discussionmentioning

confidence: 99%

Placental circulating T cells: a novel, allogeneic CAR-T cell platform with preserved T-cell stemness, more favorable cytokine profile, and durable efficacy compared to adult PBMC-derived CAR-T

Ruggeri Barbaro,

Drashansky,

Tess

et al. 2024

J Immunother Cancer

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BackgroundChimeric antigen receptor (CAR)-T cell quality and stemness are associated with responsiveness, durability, and memory formation, which benefit clinical responses. Autologous T cell starting material across patients with cancer is variable and CAR-T expansion or potency can fail during manufacture. Thus, strategies to develop allogeneic CAR-T platforms including the identification and expansion of T cell subpopulations that correspond with CAR-T potency are an active area of investigation. Here, we compared CAR-T cells generated from healthy adult peripheral blood T cells versus placental circulating T (P-T) cells.MethodsCAR-T cells from healthy adult peripheral blood mononuclear cells (PBMCs) and P-T cells were generated using the same protocol. CAR-T cells were characterized in detail by a combination of multiparameter flow cytometry, functional assays, and RNA sequencing. In vivo antitumor efficacy and persistence of CAR-T cells were evaluated in a Daudi lymphoma xenograft model.ResultsP-T cells possess stemness advantages compared with T cells from adult PBMCs. P-T cells are uniformly naïve prior to culture initiation, maintain longer telomeres, resist immune checkpoint upregulation, and resist further differentiation compared with PBMC T cells during CD19 CAR-T manufacture. P-T CD19 CAR-T cells are equally cytotoxic as PBMC-CD19 CAR-T cells but produce less interferon gamma in response to lymphoma. Transcriptome analysis shows P-T CD19 CAR-T cells retain a stem-like gene signature, strongly associate with naïve T cells, an early memory phenotype, and a unique CD4 T cell signature compared with PBMC-CD19 CAR-T cells, which enrich for exhaustion and stimulated memory T cell signatures. Consistent with functional data, P-T CD19 CAR-T cells exhibit attenuated inflammatory cytokine and chemokine gene signatures. In a murine in vivo model, P-T CD19 CAR-T cells eliminate lymphoma beyond 90 days. PBMC-CD19 CAR-T cells provide a non-durable benefit, which only delays disease onset.ConclusionWe identified characteristics of T cell stemness enriched in P-T CD19 CAR-T which are deficient in PBMC-derived products and translate into response durability in vivo. Our findings demonstrate that placental circulating T cells are a valuable cell source for allogeneic CAR-T products. Stemness advantages inherent to P-T cells translate to in vivo persistence advantages and long-term durable activity.

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“…Dickinson et al. ( 68 ) utilized the T-charge platform to generate a novel autologous CD19-CAR-T cell therapy (YTB323), which shared the same CAR construct as tisagenleucel (clinical phase I/II). Notably, the findings demonstrated that YTB323 could be manufactured within 2 days, while preserving T cell stemness, and exhibited enhanced in vivo expansion and anti-tumor efficacy at a lower dose.…”

Section: Crispr/cas9 Technology and Pcar-t Cellsmentioning

confidence: 99%

Revolutionizing cancer treatment: enhancing CAR-T cell therapy with CRISPR/Cas9 gene editing technology

Tao,

Han,

Bai

et al. 2024

Front. Immunol.

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CAR-T cell therapy, a novel immunotherapy, has made significant breakthroughs in clinical practice, particularly in treating B-cell-associated leukemia and lymphoma. However, it still faces challenges such as poor persistence, limited proliferation capacity, high manufacturing costs, and suboptimal efficacy. CRISPR/Cas system, an efficient and simple method for precise gene editing, offers new possibilities for optimizing CAR-T cells. It can increase the function of CAR-T cells and reduce manufacturing costs. The combination of CRISPR/Cas9 technology and CAR-T cell therapy may promote the development of this therapy and provide more effective and personalized treatment for cancer patients. Meanwhile, the safety issues surrounding the application of this technology in CAR-T cells require further research and evaluation. Future research should focus on improving the accuracy and safety of CRISPR/Cas9 technology to facilitate the better development and application of CAR-T cell therapy. This review focuses on the application of CRISPR/Cas9 technology in CAR-T cell therapy, including eliminating the inhibitory effect of immune checkpoints, enhancing the ability of CAR-T cells to resist exhaustion, assisting in the construction of universal CAR-T cells, reducing the manufacturing costs of CAR-T cells, and the security problems faced. The objective is to show the revolutionary role of CRISPR/Cas9 technology in CAR-T cell therapy for researchers.

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A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-cell Stemness Shows Enhanced CAR T-cell Efficacy in Preclinical and Early Clinical Development

Cited by 23 publications

References 33 publications

Making drugs from T cells: The quantitative pharmacology of engineered T cell therapeutics

Making drugs from T cells: The quantitative pharmacology of engineered T cell therapeutics

Placental circulating T cells: a novel, allogeneic CAR-T cell platform with preserved T-cell stemness, more favorable cytokine profile, and durable efficacy compared to adult PBMC-derived CAR-T

Revolutionizing cancer treatment: enhancing CAR-T cell therapy with CRISPR/Cas9 gene editing technology

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