Nicholas Fraser

Background: Glioblastoma is the most common malignant brain cancer in adults worldwide totaling 60% of adult brain tumors.³ There is no current cure, however, the standard of care includes radiation therapy and chemotherapy.² The median survival post-surgical resection is 14 months with a 0% chance of survival.^1,2,3 90% of glioblastoma tumors are de novo and emerge as a G2 checkpoint dysregulation of receptor tyrosine kinases. CD47 has been highlighted as a significant protein involved in the survival and proliferation of glioblastoma cells.³ CD47 presents as an immune checkpoint inhibitor that silences macrophagic and innate immune responses.⁵ However, anti-CD47 antibodies have demonstrated successful inhibition of CD47 antibodies in in vitro studies and in vivo rat models. These anti-CD47 antibodies have been used with current therapeutics to prove more effective inhibition of glioblastoma cells.^6,7,8

Objective: To provide a literature review that analyzes the mechanisms of glioblastoma cell proliferation and the subsequent therapeutic approaches in sight of identifying possible strategies to effectively inhibit all glioblastoma cell proliferation.

Search Methods: An online search of the PubMed database was performed with the years 2018-2024 filtered using the keywords: “CD47”, “Glioblastoma”, “Anti-CD47 antibodies”, “Combination Therapies”, and “Lipid Nanoparticles”.

Results: Initial studies conclude that CD47 protein is elevated in glioblastoma cell lines when compared to controls.³ Further targeted inhibition of the PI3K/AKT pathway provided evidence that the mechanism of CD47 action is through activation of the PI3K/AKT signaling cascade.^3,4,5 Subsequent research assessed the inhibitory effects of anti-CD47 antibodies on proliferation of glioblastoma cells as well as the immune response to the antibodies.^3,4,5 Not only did the anti-CD47 antibodies prevent inhibition of the G2 checkpoint, but they also enhanced the M2 macrophagic response, decreased the M2:M1 macrophage ratio, and boosted the immunological memory response with natural killer and T-cell activation.⁵ Additionally, When combined with novel therapeutic approaches to glioblastoma treatments (radiation therapy and chemotherapy), anti-CD47 antibodies demonstrated significantly more success than any monotherapeutic approach itself or solely the anti-CD47 antibody approach.^6,7,8

Conclusion: Research has highlighted CD47 as a significant protein involved in glioblastoma cell proliferation. Anti-CD47 antibodies have demonstrated significant inhibition of glioblastoma cell growth and proliferation. These antibodies work through targeting both the innate and memory immune responses with macrophage, natural killer cell, and T-cell activation. When combined with novel approaches, the antibodies yield an even greater tumor cell inhibition than any current monotherapy or antibody itself.

Works Cited:

1. Ma R, Taphoorn MJB, Plaha P. Advances in the management of glioblastoma. J Neurol Neurosurg Psychiatry. 2021;92(10):1103-1111. doi:10.1136/jnnp-2020-325334
2. Wen PY, Weller M, Lee EQ, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol. 2020;22(8):1073-1113. doi:10.1093/neuonc/noaa106
3. Liu X, Wu X, Wang Y, et al. CD47 Promotes Human Glioblastoma Invasion Through Activation of the PI3K/Akt Pathway. Oncol Res. 2019;27(4):415-422. doi:10.3727/096504018X15155538502359
4. Huang CY, Ye ZH, Huang MY, Lu JJ. Regulation of CD47 expression in cancer cells. Transl Oncol. 2020;13(12):100862. doi:10.1016/j.tranon.2020.100862
5. Liu X, Zhang H, Wang C, et al. Tumor-selective Blockade of CD47 Signaling with CD47 Antibody for Enhanced Anti-tumor Activity in Malignant Meningioma. Curr Neuropharmacol. 2023;21(10):2159-2173. doi:10.2174/1570159X21666230511123157
6. Cao A, Jiaqing Yi, Xinyan Tang, et al. CD47-blocking Antibody ZL-1201 Promotes Tumor-associated Macrophage Phagocytic Activity and Enhances the Efficacy of the Therapeutic Antibodies and Chemotherapy. Cancer Research Communications 2022; 2(11): 1404–1417. https://doi.org/10.1158/2767-9764.CRC-22-0266
7. Ye L, Lv W, He W, et al. Reduced malignant glioblastoma recurrence post-resection through the anti-CD47 antibody and Temozolomide co-embedded in-situ hydrogel system. J Control Release. 2023;359:224-233. doi:10.1016/j.jconrel.2023.05.046
8. Zhang P, Rashidi A, Zhao J, et al. STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma. Nat Commun. 2023;14(1):1610. Published 2023 Mar 23. doi:10.1038/s41467-023-37328-9