The Outcome of <i>Ex Vivo</i> TIL Expansion Is Highly Influenced by Spatial Heterogeneity of the Tumor T-Cell Repertoire and Differences in Intrinsic <i>In Vitro</i> Growth Capacity between T-Cell Clones

Poschke, Isabel; Hassel, Jessica C.; Rodriguez-Ehrenfried, Aaron; Lindner, Katharina A.M.; Heras-Murillo, Ignacio; Appel, Lena M.; Lehmann, Johanna; Lövgren, Tanja; Wickström, Stina L.; Lauenstein, Claudia; Roth, Jasmin; König, A.; Haanen, John B.A.G.; Berg, Joost van den; Kiessling, Rolf; Bergmann, Frank; Floßdorf, Michael; Strobel, Oliver; Offringa, Rienk

doi:10.1158/1078-0432.ccr-19-3845

Cited by 60 publications

(48 citation statements)

References 49 publications

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“…As these cancer-specific T cells become less responsive to interleukin-2 (IL-2), which mediates T-cell expansion, they might become diluted by bystander T cells during the process of expansion in TIL-ACT, with an overall loss of TCR repertoire. 15,191,192 However, despite their functional impairment, it is widely appreciated that exhausted T cells are often tumour-specific and can still retain some control over tumour growth, as shown by the great clinical effect of blocking programmed death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) axis in solid tumours. 193,194 Exhausted T cells express increased levels of inhibitory immune checkpoint molecules, such as PD-1, CTLA-4, LAG3 and TIM3, 195 and decreased levels of the adhesion/ costimulatory molecule CD2, both of which might attenuate anti-tumour T-cell responses in tumours.…”

Section: Ex Vivo Drug Modulation Modifications Of Culturing Conditionmentioning

confidence: 99%

Promises and challenges of adoptive T-cell therapies for solid tumours

et al. 2021

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Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

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Section: Ex Vivo Drug Modulation Modifications Of Culturing Conditionmentioning

confidence: 99%

Promises and challenges of adoptive T-cell therapies for solid tumours

et al. 2021

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“…Of note, comparison of the use of allogeneic versus autologous feeder cells during the TIL expansion phase revealed that both have a similar risk of emergence of new TCR clonotypes. 31 Cells were passaged when multiple clusters of dividing T cells were observed, which was usually once or twice during the two-week REP culture period. The expanded T cells were cryopreserved in freezing medium.…”

Section: Til Culturementioning

confidence: 99%

T cells expanded from renal cell carcinoma display tumor-specific CD137 expression but lack significant IFN-γ, TNF-α or IL-2 production

et al. 2021

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Metastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies. As only a subset of RCC patients respond, alternative strategies should be explored. Patients refractory to anti-PD-1 therapy may benefit from autologous tumor-infiltrating lymphocyte (TIL) therapy. Even though efficient TIL expansion was reported from RCC lesions, it is not well established how many RCC TIL products are tumor-reactive, how well they produce pro-inflammatory cytokines in response to autologous tumors, and whether their response correlates with the presence of specific immune cells in the tumor lesions. We here compared the immune infiltrate composition of RCC lesions with that of autologous kidney tissue of 18 RCC patients. Tcell infiltrates were increased in the tumor lesions, and CD8 + Tcell infiltrates were primarily of effector memory phenotype. Nine out of 16 (56%) tested TIL products we generated were tumor-reactive, as defined by CD137 upregulation after exposure to autologous tumor digest. Tumor reactivity was found in particular in TIL products originating from tumors with ahigh percentage of infiltrated Tcells compared to autologous kidney, and increased CD25 expression on CD8 + Tcells. Importantly, although TIL products had the capacity to produce the key effector cytokines IFN-γ, TNF-α or IL-2, they failed to produce significant amounts in response to autologous tumor digests. In conclusion, TIL products from RCC lesions contain tumor-reactive Tcells. Their restricted tumor-specific cytokine production requires further investigation of immunosuppressive factors in RCC and subsequent optimization of RCC-derived TIL culture conditions.

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“…In a recent study, Schober and colleagues studied TCR repertoire evolution in the context of latent CMV infection and found that, although high-affinity TCRs dominated T cell responses at early times after infection, low affinity TCRs emerged over time, owing to cellular differentiation and senescence (and not exhaustion) of high affinity ones (124). In a recent publication, Poschke and coauthors exploited TCR deep sequencing to characterize TILs before and after in vitro culture and found that dominant T cell clones were lost during TIL culture because of poor expansion potential, in favor of less represented ones (125). The authors argue that spatial heterogeneity of the tumor T cell repertoire, as well as differences in intrinsic in vitro growth capacity between individual T cell clones, influenced the T cell preparation.…”

Section: Tcr Affinity/aviditymentioning

confidence: 99%

To Remember or to Forget: The Role of Good and Bad Memories in Adoptive T Cell Therapy for Tumors

Mondino

Manzo

2020

Front. Immunol.

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The generation of immunological memory is a hallmark of adaptive immunity by which the immune system "remembers" a previous encounter with an antigen expressed by pathogens, tumors, or normal tissues; and, upon secondary encounters, mounts faster and more effective recall responses. The establishment of T cell memory is influenced by both cell-intrinsic and cell-extrinsic factors, including genetic, epigenetic and environmental triggers. Our current knowledge of the mechanisms involved in memory T cell differentiation has instructed new opportunities to engineer T cells with enhanced anti-tumor activity. The development of adoptive T cell therapy has emerged as a powerful approach to cure a subset of patients with advanced cancers. Efficacy of this approach often requires long-term persistence of transferred T cell products, which can vary according to their origin and manufacturing conditions. Host preconditioning and post-transfer supporting strategies have shown to promote their engraftment and survival by limiting the competition with a hostile tumor microenvironment and between pre-existing immune cell subsets. Although in the general view pre-existing memory can confer a selective advantage to adoptive T cell therapy, here we propose that also "bad memories"-in the form of antigen-experienced T cell subsets-co-evolve with consequences on newly transferred lymphocytes. In this review, we will first provide an overview of selected features of memory T cell subsets and, then, discuss their putative implications for adoptive T cell therapy.

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The Outcome of Ex Vivo TIL Expansion Is Highly Influenced by Spatial Heterogeneity of the Tumor T-Cell Repertoire and Differences in Intrinsic In Vitro Growth Capacity between T-Cell Clones

Abstract: The outcome of ex vivo TIL expansion is highly influenced by spatial heterogeneity of the tumor Tcell repertoire and differences in intrinsic in vitro growth capacity between T-cell clones AUTHORS -

Cited by 60 publications

References 49 publications

Promises and challenges of adoptive T-cell therapies for solid tumours

Promises and challenges of adoptive T-cell therapies for solid tumours

T cells expanded from renal cell carcinoma display tumor-specific CD137 expression but lack significant IFN-γ, TNF-α or IL-2 production

To Remember or to Forget: The Role of Good and Bad Memories in Adoptive T Cell Therapy for Tumors

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