Researchers present an alternative approach for attenuating cell-surface receptor signaling, termed receptor inhibition by phosphatase recruitment.
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Midkine was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways.
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Cerezo-Wallis, D., Contreras-Alcalde, M., Troulé, K., Catena, X., Mucientes, C., Calvo, T. G., Cañón, E., Tejedo, C., Pennacchi, P. C., Hogan, S., Kölblinger, P., Tejero, H., Chen, A. X., Ibarz, N., Graña-Castro, O., Martinez, L., Muñoz, J., Ortiz-Romero, P., Rodriguez-Peralto, J. L., … Soengas, M. S. (2020). Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state. Nature Medicine, 1–13. https://doi.org/10.1038/s41591-020-1073-3 Cite
Merck announced that the FDA has approved an expanded label for KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma.
[Merck & Co., Inc.]
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Researchers undertook a novel combination therapy using rAd-p53 in situ gene therapy and immunotherapy with immune checkpoint inhibitor anti-PD-1 antibody for urogenital cancers. Three mouse syngeneic tumor cell lines, TRAMP-C2 (prostate), MBT-2 (bladder) and Renca (kidney) were used.
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Kunimura, N., Kitagawa, K., Sako, R., Narikiyo, K., Tominaga, S., Bautista, D. S., Xu, W., Fujisawa, M., & Shirakawa, T. (2020). Combination of rAd-p53 in situ gene therapy and anti-PD-1 antibody immunotherapy induced anti-tumor activity in mouse syngeneic urogenital cancer models. Scientific Reports, 10(1), 17464. https://doi.org/10.1038/s41598-020-74660-2 Cite
Researchers identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells.
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Galletti, G., De Simone, G., Mazza, E. M. C., Puccio, S., Mezzanotte, C., Bi, T. M., Davydov, A. N., Metsger, M., Scamardella, E., Alvisi, G., De Paoli, F., Zanon, V., Scarpa, A., Camisa, B., Colombo, F. S., Anselmo, A., Peano, C., Polletti, S., Mavilio, D., … Lugli, E. (2020). Two subsets of stem-like CD8 + memory T cell progenitors with distinct fate commitments in humans. Nature Immunology, 1–11. https://doi.org/10.1038/s41590-020-0791-5 Cite
Scientists evaluated pembrolizumab concentrations and PD-1 blockade on T cells in the cerebrospinal fluid after intravenous administration. Cerebrospinal fluid and blood samples were collected from 10 adult patients with high-grade gliomas who were participating in clinical trials of intracranially administered chimeric antigen receptor T cells and intravenous pembrolizumab.
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Portnow, J., Wang, D., Blanchard, M. S., Tran, V., Alizadeh, D., Starr, R., Dodia, R., Chiu, V., Brito, A., Kilpatrick, J., McNamara, P., Forman, S. J., Badie, B., Synold, T. W., & Brown, C. E. (2020). Systemic Anti–PD-1 Immunotherapy Results in PD-1 Blockade on T Cells in the Cerebrospinal Fluid. JAMA Oncology. https://doi.org/10.1001/jamaoncol.2020.4508 Cite
Cancer immunotherapy using immune-checkpoint blockade has displayed promising clinical effects, but prevalent antibody-based inhibitors face multiple challenges such as low response rate, acquired resistance, and adverse effects.
Scientists generated a novel anti-CD19 CAR expressing PD-1/CD28 chimeric switch-receptor. They then conducted a Phase Ib study to evaluate safety and efficacy of CD19-PD-1/CD28-CAR T cells in the treatment of PD-L1+ B-cell lymphoma.
[Clinical Cancer Research]
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Liu, H., Lei, W., Zhang, C., Yang, C., Wei, J., Guo, Q., Guo, X., Chen, Z., Lu, Y., Young, K. H., Lu, Z., & Qian, W. (2020). CD19-Specific CAR-T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor is Effective in Patients with PD-L1 Positive B-Cell Lymphoma. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-20-1457 Cite
The authors discuss the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade in combination with conventional chemotherapy, targeted therapy or immunotherapy. Meanwhile, they illustrate their underlying mechanisms in regulating the process of the cancer-immunity cycle, providing the rationale for the PD-1/PD-L1 blockade-based combination therapy.
[Pharmacology & Therapeutics]
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Oncolytic virus therapy can potentially overcome resistance to immunotherapy in prostate cancers by transforming cold tumors into ‘hot’, immune cell-infiltrated tumors. Scientists investigated whether the combination of intratumoural oncolytic reovirus, followed by targeted blockade of PD-1 checkpoint inhibition and/or the immunomodulatory CD73/Adenosine system could enhance anti-tumor immunity.
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Annels, N. E., Simpson, G. R., Denyer, M., Arif, M., Coffey, M., Melcher, A., Harrington, K., Vile, R., & Pandha, H. (2020). Oncolytic reovirus-mediated recruitment of early innate immune response reverses immunotherapy-resistance in prostate tumours by inducing a T-cell inflamed microenvironment. Molecular Therapy - Oncolytics, 0(0). https://doi.org/10.1016/j.omto.2020.09.010 Cite
Researchers found that T lymphocytes accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells.
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Yu, Y.-R., Imrichova, H., Wang, H., Chao, T., Xiao, Z., Gao, M., Rincon-Restrepo, M., Franco, F., Genolet, R., Cheng, W.-C., Jandus, C., Coukos, G., Jiang, Y.-F., Locasale, J. W., Zippelius, A., Liu, P.-S., Tang, L., Bock, C., Vannini, N., & Ho, P.-C. (2020). Disturbed mitochondrial dynamics in CD8 + TILs reinforce T cell exhaustion. Nature Immunology, 1–12. https://doi.org/10.1038/s41590-020-0793-3 Cite