High-Risk Neuroblastoma Challenges and Opportunities for Antibody-Based Cellular Immunotherapy
Abstract
:1. Introduction
2. Biological Features of Neuroblastoma in Risk Assignment and Treatment
3. Immunological Features and Tumor Microenvironment in Neuroblastoma (Table 1)
Limitations | Opportunities | |
---|---|---|
Neuroblastoma (NB) | Low MHC class I expression Low tumor mutational burden (TMB) | Adoptive Cell Therapy. GD2 is a reliable tumor-associated surface antigen, an ideal target for novel antibody-based therapeutics. |
Tumor micro-environment (TME) | Immature microvasculature Excess immunosuppressive cells Immunosuppressive pathways Few tumor-infiltrating lymphocytes (TILs) | VEGF inhibitors. Antibody-depletion protocols. Immune checkpoint blockades. Adoptive Cell Therapy using ex vivo expanded TIL, chimeric antigen receptor modified T cells (CARTs) and T cells armed ex vivo with T-BsAb. |
4. Immunotherapies for Neuroblastoma: Monoclonal Antibody, Chimeric Antigen Receptor T Cells, and Bispecific Antibodies
5. Ex Vivo Armed T Cell with Bispecific Antibodies (EATs)
5.1. Optimizing Bispecific Antibody Platform for EATs
5.1.1. Targeting the TME with EATs: The IMPROVE Strategy 1
5.1.2. Targeting Multi-Antigen with EATs: The IMPROVE Strategy 2
6. Conclusions
7. Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Tumor Infiltrating Lymphocytes (TILs) | Chimeric Antigen Receptor T Cells (CARTs) | Bispecific Antibody (BsAb) PLUS T Cells | Ex Vivo BsAb-Armed T Cells (EATs) | |
---|---|---|---|---|
Description | Natural TILs ex vivo expanded | T cells transfected with Chimeric Antigen Receptor | BsAb targets T cells to tumor (BsAb as drug) | T cells coated with BsAb to target tumor (T cell as drug) |
Traffic to Tumor | Unknown | Good | Good | Good |
Tumor-Associated Antigens (TAAs) | Multiple | Single | Single | Multiple |
Dominant Lymphocyte Subset | CD8+ | CD8+ | CD8+ | CD8+ and CD4+ |
MHC class I dependent | Yes | No | No | No |
Additional Co-Stimulator Signals Required | Yes | Yes | No | No |
Cytokine Storm | Yes | Yes | Yes | Minimized |
Persistence | Life Time | Life Time | <1 month | <1 month |
Exhaustion | Yes | Yes | Less | Less |
Toxicity | CRS | CRS, ICANS | CRS | CRS |
Manufacture (Ease/Cost) | Complex/Expensive | Complex/Expensive | Facile/Affordable | Facile/Affordable |
Compatible with Other Biologics and Drugs | n/a | Yes | Yes | Yes |
Current Stage | Pre-clinical | Early clinical | Pre-clinical | Pre-clinical |
Antigen | Cancer Patients/Xenographs/Cell Lines | Significance Finding | Ref |
---|---|---|---|
GD2, HER2, EGFR CD20 | Breast, prostate, pancreatic, non-Hodgkin lymphoma, multple myeloma | Pre-clinical studies: BsAb-armed T cells showed antigen specific proliferation, cytotoxicity and Th1 cytokine release. Phase I and II studies: BsAb successfully redirected armed T cells for non-MHC restricted cytotoxicity for anti-tumor immune response in several malignancies. | [55,71,72,73,74,75] |
GD2 | Neuroblastoma, osteosarcoma | Phase I study. GD2 BsAb-armed T cells stimulated endogenous T and NK cells for a safe and effective anti-GD2 positive immune response against GD2 positive pediatric malignancies. | [76] |
GD2 CD33 | Melanoma, neuroblastoma | Bs Ab Platform optimization: 2 + 2, interdomain distance, cis-trans configuration, affinity, valency, avidity, and heterodimeric optimized forms improved cytotoxicity (up to 2000 fold) with enhanced cytokine release and in vivo anti-tumor responses. | [64] |
STEAP1 | Ewing sarcoma, prostate cancer and canine osteosarcoma cell lines | Superior format over other antibody formats: 2 + 2 IgG-[L]-scFc platform increased TILs into tumor (30 fold) for a superior anti-tumor effects as BsAb alone or ex vivo armed T cells (EATs). | [68] |
GD2 HER2 | Melanoma, osteosarcoma, small cell lung cancer | Reverse immunosuppressive TIMs: 2 + 2 IgG[L]-scFv platform increased TIL as well as tumor immunosuppressive myeloid (TIM) cells into the TME. Combining depleting protocols to reduce TIMs further increased T cell infiltration and persistence in TME for superior tumor control and improved survival. | [14] |
GD2, HER2, GPC3 | Neuroblastoma and osteosarcoma. | Normalize neovasculature (VEGF and VEGFR2). Vascular endothelial growth factor (VEGF) blockade improved BsAb-driven intratumoral T cell infiltration (2–8 fold), with more CD8 TIL (than CD4) to yield superior anti-tumor effects without added toxicities. | [14] |
GD2 HER2 | Osteosarcoma | Immune checkpoint inhibitors (PD1 and PD-L1): BsAb alone or T cells armed with anti-GD2 or anti-HER2 BsAb exerted potent anti-tumor effects in vitro and in vivo. Anti-PDL-1 added sequentially and continuously enhanced BsAb-armed T cells function in vivo for improved tumor control and survival. | [14] |
GD2 HER 2 | Neuroblastoma, osteosarcoma, primitive neuroectodermal tumor, prostate cancer and melanoma | EATs (Ex vivo armed T cells) alternative to CART: EATs using BsAb on IgG-[L]-scFv-platform exerted safe potent anti-tumor activities against a spectrum of human cancer targets. | [61] |
GD2 HER2 CD33 STEAP-1 PSMA | Neuroblastoma, osteosarcoma, primitive neuroectodermal tumor cell line, breast cancer | Overcoming tumor heterogeneity with multispecificity BsAb: BsAb built on IgG-[L]-scFv can support mutli-EAT strategies (T cells armed with BsAb specific for two tumor-associated antigens). Multi-EAT strategies can overcome the heterogeneity associated with tumor evolution. Multi-EAT retains and delivers multiple antigen specificity for adequate anti-tumor potency to suppress tumor growth and without clinical toxcities. This approach prevents clonal escape and prevents cancer resistance. | [14] |
77EGFR, HER CD33 | Pancreatic ductal adenocarcinoma | Heterodimeric T-BsAb (HDTV) avidity and affinity tuning: 2 + 2 Ig-[L]-scFv T- BsAb format with two anti-CD3 scFv engaged T cells with bivalent binding to tumor antigens with both Fab arms demostrated high avidity (and efficient infiltration of polyclonal T cells into TME for potent T-mediated anti-tumor effects. | [77] |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Persaud, N.V.; Park, J.A.; Cheung, N.K.V. High-Risk Neuroblastoma Challenges and Opportunities for Antibody-Based Cellular Immunotherapy. J. Clin. Med. 2024, 13, 4765. https://doi.org/10.3390/jcm13164765
Persaud NV, Park JA, Cheung NKV. High-Risk Neuroblastoma Challenges and Opportunities for Antibody-Based Cellular Immunotherapy. Journal of Clinical Medicine. 2024; 13(16):4765. https://doi.org/10.3390/jcm13164765
Chicago/Turabian StylePersaud, Natasha V., Jeong A. Park, and Nai Kong V. Cheung. 2024. "High-Risk Neuroblastoma Challenges and Opportunities for Antibody-Based Cellular Immunotherapy" Journal of Clinical Medicine 13, no. 16: 4765. https://doi.org/10.3390/jcm13164765