Enhancing Lung Cancer Treatment with Immunogenic Chemotherapy and CAR-T Cells
Summary
Adoptive therapy utilizing CAR-T cells has shown promising results in treating hematologic malignancies, however, it is not as effective in treating epithelial malignancies which pose a higher mortality rate. In patients with breast and lung cancer, CAR-T cells targeting ROR1 are unable to effectively infiltrate tumors and become dysfunctional. To enhance the efficacy of this therapy, they conducted an experiment on a KrasLSL-G12D/+;p53f/f model of lung adenocarcinoma, which was engineered to express the ROR1 target. The results showed that after lymphodepletion with cyclophosphamide, the transfer of murine ROR1 CAR-T cells temporarily controlled tumor growth but similarly to the patients, it was poorly infiltrated and lost function. Supplementing the lymphodepletion regimen with oxaliplatin activated the tumor macrophages to express T-cell-recruiting chemokines, leading to improved CAR-T cell infiltration and enhanced tumor sensitivity to anti-PD-L1. The combination therapy of Ox/Cy and anti-PD-L1 produced a synergistic effect, significantly improving the control and survival of the tumors through CAR-T cell-mediated means, providing a new strategy for increasing the efficacy of CAR-T cell therapy in clinical practice.
Fig.1 Graphical abstract. (Srivastava, 2021)
Research Criteria
CAR T cells have been effective in treating hematologic cancers but not solid tumors. This is due to issues like poor T-cell migration, tumor-induced immunosuppression, and inhibitory receptor production. A model mimicking the tumor environment has been established to tackle these challenges. The KrasLSL-G12D/+;p53f/f lung adenocarcinoma model was modified to express ROR1 for testing CAR-T cell efficacy in solid tumors. However, the KPROR1 model showed limited invasion and temporary efficacy of murine ROR1 CAR-T cells. The purpose of the study is to find ways to enhance CAR-T cell trafficking to solid tumors.
Sample Type
Cells from mouse solid tumor tissues.
Result—Ox/Cy Activates Expression of T-Cell-Recruiting Chemokines by Tumor Macrophages
The researchers treated tumor-bearing mice with Ox/Cy or a vehicle, then administered CAR-T cells. They collected single-cell RNA-seq data from the tumors at two different time points and analyzed cell populations. The results showed that Ox/Cy increased the frequency of T cells in the tumors, with the CAR-T cell expression limited to cells from the infusion product. The T cells were activated in vivo and expressed activation-associated transcripts. The NK cell cluster was also composed of cells from mice treated with Ox/Cy and expressed transcripts associated with effector function.
Fig.2 Ox/Cy enhances the accumulation of tumor-infiltrating CAR-T cells with an activated phenotype. (Srivastava, 2021)
Ox/Cy treatment caused significant changes in the mononuclear phagocyte (MNP) cluster, with division into three cell types (macrophages, DCs, and monocytes) using a neural network. The macrophages in particular grouped into four subclusters based on their activation states, induced by Ox/Cy and/or CAR-T cells. These subclusters were distinguished by the expression of different markers (Siglecf, Mrc1, and Nos2). Cluster 2, made up of cells from mice 6 h after Ox/Cy treatment, showed increased activation, cytokine, and chemokine expression, and TLR signaling gene sets compared to the other clusters, suggesting early activation of tumor macrophages by Ox/Cy.
Fig.3 Ox/Cy activates expression of T-cell-recruiting chemokines by tumor macrophages. (Srivastava, 2021)
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Reference
- Srivastava, S.; et al. Immunogenic chemotherapy enhances recruitment of CAR-T cells to lung tumors and improves antitumor efficacy when combined with checkpoint blockade. Cancer Cell. 2021, 39(2): 193-208.
