bims-tuinly 2024-10-06 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2024–10–06
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Mathematical modeling insights into improving CAR T cell therapy for solid tumors with bystander effects.
Syngeneic Mouse Models for Pre-Clinical Evaluation of CAR T Cells.
Cancer immunotherapy by γδ T cells.
Advancing Cholangiocarcinoma Care: Insights and Innovations in T Cell Therapy.
Spatial heterogeneity of infiltrating immune cells in the tumor microenvironment of non-small cell lung cancer.
DSP-0509, a TLR7 agonist, exerted synergistic anti-tumor immunity combined with various immune therapies through modulating diverse immune cells in cancer microenvironment.
Crosstalk of T cells within the ovarian cancer microenvironment.
Peptide-MHC-targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells.

NPJ Syst Biol Appl. 2024 Sep 28. 10(1): 105

Mathematical modeling insights into improving CAR T cell therapy for solid tumors with bystander effects.

Erdi Kara, Trachette L Jackson, Chartese Jones, Rockford Sison, Reginald L McGee Ii.

As an adoptive cellular therapy, Chimeric Antigen Receptor T cell (CAR T cell) therapy has shown remarkable success in hematological malignancies but only limited efficacy against solid tumors. Compared with blood cancers, solid tumors present a series of challenges that ultimately combine to neutralize the function of CAR T cells. These challenges include, but are not limited to, antigen heterogeneity - variability in the expression of the antigen on tumor cells, as well as trafficking and infiltration into the solid tumor tissue. A critical question for solving the heterogeneity problem is whether CAR T therapy induces bystander effects, such as antigen spreading. Antigen spreading occurs when CAR T cells activate other endogenous antitumor CD8 T cells against antigens that were not originally targeted. In this work, we develop a mathematical model of CAR T cell therapy for solid tumors that considers both antigen heterogeneity and bystander effects. Our model is based on in vivo treatment data that includes a mixture of target antigen-positive and target antigen-negative tumor cells. We use our model to simulate large cohorts of virtual patients to better understand the relationship involving bystander killing. We also investigate several strategies for enhancing bystander effects, thus increasing CAR T cell therapy's overall efficacy for solid tumors.

DOI: https://doi.org/10.1038/s41540-024-00435-4
Cancers (Basel). 2024 Sep 18. pii: 3186. [Epub ahead of print]16(18):

Syngeneic Mouse Models for Pre-Clinical Evaluation of CAR T Cells.

Eman N Ahmed, Lauren C Cutmore, John F Marshall.

  Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies. Unfortunately, this improvement has yet to be translated into the solid tumor field. Current immunodeficient models used in pre-clinical testing often overestimate the efficacy of CAR T cell therapy as they fail to recapitulate the immunosuppressive tumor microenvironment characteristic of solid tumors. As CAR T cell monotherapy is unlikely to be curative for many solid tumors, combination therapies must be investigated, for example, stromal remodeling agents and immunomodulators. The evaluation of these combination therapies requires a fully immunocompetent mouse model in order to recapitulate the interaction between the host's immune system and the CAR T cells. This review will discuss the need for improved immunocompetent murine models for the pre-clinical evaluation of CAR T cells, the current use of such models and future directions.

Keywords:  CAR T cells; adoptive cellular therapy; combination therapy; immunotherapy; solid tumors; syngeneic models

DOI:  https://doi.org/10.3390/cancers16183186
Science. 2024 Oct 04. 386(6717): eabq7248

Cancer immunotherapy by γδ T cells.

Adrian Hayday, Julie Dechanet-Merville, Jamie Rossjohn, Bruno Silva-Santos.

The premise of cancer immunotherapy is that cancers are specifically visible to an immune system tolerized to healthy self. The promise of cancer immunotherapy is that immune effector mechanisms and immunological memory can jointly eradicate cancers and inoperable metastases and de facto vaccinate against recurrence. For some patients with hitherto incurable diseases, including metastatic melanoma, this promise is being realized by game-changing immunotherapies based on αβ T cells. Today's challenges are to bring benefit to greater numbers of patients of diverse ethnicities, target more cancer types, and achieve a cure while incurring fewer adverse events. In meeting those challenges, specific benefits may be offered by γδ T cells, which compose a second T cell lineage with distinct recognition capabilities and functional traits that bridge innate and adaptive immunity. γδ T cell-based clinical trials, including off-the-shelf adoptive cell therapy and agonist antibodies, are yielding promising results, although identifiable problems remain. In addressing those problems, we advocate that immunotherapies be guided by the distinctive biology of γδ T cells, as elucidated by ongoing research.

DOI: https://doi.org/10.1126/science.abq7248
Cancers (Basel). 2024 Sep 23. pii: 3232. [Epub ahead of print]16(18):

Advancing Cholangiocarcinoma Care: Insights and Innovations in T Cell Therapy.

Neda Dadgar, Arun K Arunachalam, Hanna Hong, Yee Peng Phoon, Jorge E Arpi-Palacios, Melis Uysal, Chase J Wehrle, Federico Aucejo, Wen Wee Ma, Jan Joseph Melenhorst.

  Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment.

Keywords:  CAR T cell therapy; CCA; immunotherapy; precision medicine; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cancers16183232
Transl Oncol. 2024 Oct 03. pii: S1936-5233(24)00270-5. [Epub ahead of print]50 102143

Spatial heterogeneity of infiltrating immune cells in the tumor microenvironment of non-small cell lung cancer.

Xinyue Liu, Yan Kong, Youwen Qian, Haoyue Guo, Lishu Zhao, Hao Wang, Kandi Xu, Li Ye, Yujin Liu, Hui Lu, Yayi He.

  Tumor-infiltrating lymphocytes (TILs) are essential components of the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). Still, it is difficult to describe due to their heterogeneity. In this study, five cell markers from NSCLC patients were analyzed. We segmented tumor cells (TCs) and TILs using Efficientnet-B3 and explored their quantitative information and spatial distribution. After that, we simulated multiplex immunohistochemistry (mIHC) by overlapping continuous single chromogenic IHCs slices. As a result, the proportion and the density of programmed cell death-ligand 1 (PD-L1)-positive TCs were the highest in the core. CD8+ T cells were the closest to the tumor (median distance: 41.71 μm), while PD-1+T cells were the most distant (median distance: 62.2μm), and our study found that most lymphocytes clustered together within the peritumoral range of 10-30 μm where cross-talk with TCs could be achieved. We also found that the classification of TME could be achieved using CD8+ T-cell density, which is correlated with the prognosis of patients. In addition, we achieved single chromogenic IHC slices overlap based on CD4-stained IHC slices. We explored the number and spatial distribution of cells in heterogeneous TME of NSCLC patients and achieved TME classification. We also found a way to show the co-expression of multiple molecules economically.

Keywords:  Deep learning; Immune checkpoint; Tumor microenvironment (TME); Tumor-infiltrating lymphocyte (TIL)

DOI:  https://doi.org/10.1016/j.tranon.2024.102143
Front Oncol. 2024 ;14 1410373

DSP-0509, a TLR7 agonist, exerted synergistic anti-tumor immunity combined with various immune therapies through modulating diverse immune cells in cancer microenvironment.

Yosuke Ota, Ryosaku Inagaki, Kentaro Sumida, Megumi Nakamura, Yasuhiro Nagai, Setsuko Yamamoto.

  Toll-like receptor 7 (TLR7) acts as a crucial component of the innate immune system. Upon TLR7 binding to its ligand, myeloid cells, including dendritic cells (DCs) and macrophages, are activated and play vital roles in initiating adaptive immunity. Consequently, TLR7 agonists have been employed in cancer immunotherapy. We have synthesized DSP-0509, a systemic injectable TLR7 agonist, and in this investigation, we examined the effects of DSP-0509 on tumor-infiltrating lymphocytes (TILs) utilizing single-cell RNA sequencing (scRNA-seq) in a mouse model bearing tumors. Our results demonstrated that DSP-0509 induced an expansion of immune cell populations, such as Natural Killer (NK) cells, CD4+ T cells, and CD4+ regulatory T cells (Tregs). Subsequently, we combined an Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor with DSP-0509 to enhance the antitumor efficacy by reducing Tregs, as DSP-0509 led to an increase in Treg presence within tumors. Our findings demonstrated that this combination therapy effectively reduced Treg infiltration within the tumor, leading to enhanced antitumor activity. To further prevent CD8+ T cell exhaustion, we combined DSP-0509 with an anti-PD-1 antibody and assessed the alterations in TILs using scRNA-seq. Our results indicated that the combination treatment significantly increased the cluster of CD8+ T cells expressing Gzmb, Prf1, Ctla4, and Icos, when compared to the administration of DSP-0509 alone. Additionally, we observed a marked rise in the M1-like macrophage cluster in the combination treatment group compared to the group receiving only DSP-0509. To validate the potential of modulating myeloid cells within the tumor to enhance antitumor efficacy, we combined DSP-0509 with an inhibitor targeting the receptor tyrosine kinase AXL. In bone marrow derived macrophages (BMDMs), the AXL inhibitor further amplified DSP-0509-stimulated TNFα secretion while reducing IL-10 secretion. As a final step, we evaluated the antitumor activity by combining DSP-0509 and the AXL inhibitor in an in vivo tumor model, which demonstrated increased efficacy. In summary, our study elucidated the effects of DSP-0509 on immune activity within the tumor microenvironment. These findings provided valuable insights that pave the way for the development of novel combination immunotherapy strategies.

Keywords:  AXL; DSP-0509; IDO1; TLR7 agonist; TP-0903; epacadostat; myeloid cell; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fonc.2024.1410373
Trends Cancer. 2024 Sep 27. pii: S2405-8033(24)00190-0. [Epub ahead of print]

Crosstalk of T cells within the ovarian cancer microenvironment.

Bovannak S Chap, Nicolas Rayroux, Alizée J Grimm, Eleonora Ghisoni, Denarda Dangaj Laniti.

  Ovarian cancer (OC) represents ecosystems of highly diverse tumor microenvironments (TMEs). The presence of tumor-infiltrating lymphocytes (TILs) is linked to enhanced immune responses and long-term survival. In this review we present emerging evidence suggesting that cellular crosstalk tightly regulates the distribution of TILs within the TME, underscoring the need to better understand key cellular networks that promote or impede T cell infiltration in OC. We also capture the emergent methodologies and computational techniques that enable the dissection of cell-cell crosstalk. Finally, we present innovative ex vivo TME models that can be leveraged to map and perturb cellular communications to enhance T cell infiltration and immune reactivity.

Keywords:  3D tumor models; T cell; cellular crosstalk; ovarian cancer; spatial omics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2024.09.001
bioRxiv. 2024 Sep 22. pii: 2024.09.18.613594. [Epub ahead of print]

Peptide-MHC-targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells.

Ellen J K Xu, Blake E Smith, Winiffer D Conce Alberto, Michael J Walsh, Birkley Lim, Megan T Hoffman, Li Qiang, Jiayi Dong, Andrea Garmilla, Qingyang Henry Zhao, Caleb R Perez, Stephanie A Gaglione, Connor S Dobson, Michael Dougan, Stephanie K Dougan, Michael E Birnbaum.

Tumor-infiltrating-lymphocyte (TIL) therapy has demonstrated that endogenous T cells can be harnessed to initiate an effective anti-tumor response. Despite clinical promise, current TIL production protocols involve weeks-long ex vivo expansions which can affect treatment efficacy. Therefore, additional tools are needed to engineer endogenous tumor-specific T cells to have increased potency while mitigating challenges of manufacturing. Here, we present a strategy for pseudotyping retroviral vectors with peptide-major histocompatibility complexes (pMHC) for antigen-specific gene delivery to CD8 T cells and examine the efficacy of these transduced cells in immunocompetent mouse models. We demonstrate that pMHC-targeted viruses are able to specifically deliver function-enhancing cargoes while simultaneously activating and expanding anti-tumor T cells. The specificity of these viral vectors enables in vivo engineering of tumor-specific T cells, circumventing ex vivo manufacturing processes and improving overall survival in B16F10-bearing mice. Altogether, we have established that pMHC-targeted viruses are efficient vectors for reprogramming and expanding tumor-specific populations of T cells directly in vivo , with the potential to substantially streamline engineered cell therapy production for a variety of applications.

DOI: https://doi.org/10.1101/2024.09.18.613594