Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Jeong A Park
 -- 2607 2023-08-24 07:18:04 |
2 references update
Fanny Huang
Meta information modification 2607 2023-08-28 07:03:39 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Park, J.A.; Cheung, N.V. Adoptive T Cell Immunotherapy for Osteosarcoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/48406 (accessed on 22 July 2024).
Park JA, Cheung NV. Adoptive T Cell Immunotherapy for Osteosarcoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/48406. Accessed July 22, 2024.
Park, Jeong A, Nai-Kong V. Cheung. "Adoptive T Cell Immunotherapy for Osteosarcoma" Encyclopedia, https://encyclopedia.pub/entry/48406 (accessed July 22, 2024).
Park, J.A., & Cheung, N.V. (2023, August 24). Adoptive T Cell Immunotherapy for Osteosarcoma. In Encyclopedia. https://encyclopedia.pub/entry/48406
Park, Jeong A and Nai-Kong V. Cheung. "Adoptive T Cell Immunotherapy for Osteosarcoma." Encyclopedia. Web. 24 August, 2023.
Adoptive T Cell Immunotherapy for Osteosarcoma
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms241512520

Patients with osteosarcoma often develop resistance to chemotherapeutic agents, where personalized targeted therapies should offer new hope. T cell immunotherapy as a complementary or alternative treatment modality is advancing rapidly in general, but its potential against osteosarcoma remains largely unexplored. Strategies incorporating immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) modified T cells, and T cell engaging bispecific antibodies (BsAbs) are being explored to tackle relapsed or refractory osteosarcoma. 

T cell immunotherapy osteosarcoma immune checkpoint inhibitors

1. Introduction

Bone sarcomas represent about 6% of all pediatric cancers, of which osteosarcoma makes up the majority (56%), making it the most common primary bone malignancy for children and young adults. The patients diagnosed with metastatic or relapsed osteosarcoma still have dismal outcomes despite multimodal treatment approaches such as conventional multi-agent chemotherapy, surgery, or high-dose chemotherapy with stem cell transplantation, achieving long-term survival in less than 30% of cases [1]. Moreover, given the young age of onset for osteosarcoma, the side effects of these treatments can be devastating and long-lasting. Even patients in remission can suffer from long-term complications including secondary malignancies, disfigurement (from surgery), and psychosocial trauma [2][3]. As such, there is a desperate need for more effective and less toxic therapy for both localized and metastatic high-risk osteosarcoma. Immunotherapy may offer viable alternatives. Since the reports of Dr. Coley on bacterial toxins inducing tumor regression [4], many immunotherapy attempts have been made in soft tissue and bone sarcomas, but so far without consistent or durable response [5][6]. Although interferons (IFN) are well known to have anti-angiogenic, anti-tumor, and immune-stimulating properties [5], the EURAMOS-1 clinical trial incorporating IFN-α2b as a maintenance therapy failed to show clinical benefit [7]. Monoclonal IgG antibodies targeting specific tumor surface antigens have also been tested, including trastuzumab to target HER2 (human epidermal growth factor receptor 2) [8], cetuximab to target epidermal growth factor receptor (EGFR) [9], glembatumumab vedotin (GV) to target glycoprotein nonmetastatic B (gpNMB) [10], denosumab to target the cytokine RANKL (receptor activator of NFκB ligand) (NCT02470091), and dinutuximab to target disialogangliosides (GD2) (NCT 02484443), but anti-tumor effects have been transient or inconsistent [11][12][13]. Recently, trastuzumab deruxtecan (an antibody-drug conjugate consisting of trastuzumab and topoisomerase I inhibitor deruxtecan) was FDA approved in patients with HER2-low metastatic breast cancer [14]. A phase 2 study of trastuzumab deruxtecan is ongoing for the treatment of HER2(+) osteosarcoma (NCT04616560), but the preliminary results are disappointing: seven out of eight patients showed progressive disease, while one showed a stable disease [15].
T cell immunotherapy has proven activity for many high-risk malignancies, but their efficacy against osteosarcoma remains largely unexplored. Although preclinical studies using immune checkpoint inhibitors (ICIs), antigen-specific chimeric antigen receptor (CAR), or bispecific antibody (BsAb) have demonstrated the impressive anti-tumor capacity of T cells, immunosuppressive tumor microenvironment (TME) remains a major barrier. Bone tumors, including osteosarcomas, grow in a bone microenvironment, unique among primary tumors while common for metastases with preference for the bony niche. This TME is composed of a variety of cells including bone cells (osteoblasts, osteoclasts, osteocytes), stromal cells (mesenchymal stromal cells, fibroblasts), vascular cells (endothelial cells and pericytes), immune cells (dendritic cells (DCs), T cells, tumor-associated macrophages (TAMs), myeloid-derived suppressive cells (MDSCs), and NK cells), and a mineralized extracellular matrix (ECM). Cross-talks between osteosarcoma and the TME are channeled through diverse environmental signals such as cytokines, chemokines, and soluble growth factors [13] that promote tumor growth and metastasis while simultaneously thwarting immune surveillance. This osteosarcoma-specific TME impedes T cell infiltration into tumors, accelerates immune effector cell exhaustion and anergy, and derails anti-tumor immunity, creating both a major roadblock and a potential tumor vulnerability.

2. Immune Checkpoint Inhibitors for Osteosarcoma

Upregulation of programmed cell death-1 receptor (PD-1) on CD8(+) T cells promotes T cell exhaustion and dysfunction in chronic inflammation [16][17][18][19]. PD-1 and tumor PD-L1 interaction promotes T cell tolerance through suppressing release of immunostimulatory cytokines while directly inhibiting T cell cytotoxicity [20]. ICIs reverse this process by reinvigorating cytotoxic T lymphocytes (CTLs), reviving immune response directed at neoantigens distinct from those on host tissues [21][22]. Despite the low tumor mutational burden (TMB) in pediatric cancers in general, neo-epitopes arising from genetic instability in osteosarcoma could offer potential targets for T cell-mediated cytotoxicity, potentially exploitable by ICI therapies [23][24][25].
After T cell receptor (TCR) activation, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) (CD152), type I transmembrane glycoprotein, is upregulated and constitutively expressed on CTLs and regulatory T cells (Tregs), and after binding to CD80 and CD86 with higher affinity and avidity than CD28 results in T cell suppression and DC dysfunction [26][27][28][29]. Blockade of the CTLA4 receptor increased the number of CD8(+) T cells while reducing Tregs, and combination with tumor lysate-loaded DC inhibited metastasis and prolonged survival of mice with fibrosarcoma [30].
PD-1 is also expressed on T cells following TCR engagement and activation. PD-1 and PD-L1 ligation exerts inhibitory signals for T cell activation [29]. Overexpression of PD-1 and PD-L1 and their interactions are well-characterized immune escape mechanisms of osteosarcoma [29][31][32]. Besides the direct inhibition of effector T cells, PD-1/PD-L1 interactions reduce the capacity of CD4(+) T cells to secrete IL-21 necessary for CTL response [33] and affect cytotoxicity of NK cells by reducing granzyme B secretion [34]. PD-1 was increased in circulating T cells in osteosarcoma patients, and PD-L1 expression in osteosarcoma was related to early metastasis and poorer outcome [32][35][36]. While PD-L1 density in osteosarcoma cell lines varies widely from low to high, the drug-resistant variants trend towards higher values compared to their parent counterparts [37]. A study using CRISPR/Cas9 system to target the PD-L1 gene in osteosarcoma cells revealed that PD-L1 regulates osteosarcoma growth and drug resistance [38]. The expression levels of PD-L1 correlated with TILs [37], and the blockade of PD-1/PD-L1 interactions improved the activity of osteosarcoma-reactive CTLs, resulting in an improved outcome in preclinical models [39][40]. PD-1 inhibitor could effectively control osteosarcoma pulmonary metastasis by increasing CD4(+) and CD8(+) TILs and enhancing the cytolytic activity of CD8(+) T cells in the lung [41]. Both human and murine metastatic osteosarcomas express the PD-L1, which could functionally impair tumor-infiltrating CTLs by engaging their surface PD-1. This model was supported by studies where the PD-L1 blockade improved the function of osteosarcoma TILs in vivo, decreasing tumor burden and increasing survival of mice carrying metastatic osteosarcoma [39]. The combination of triple antibodies, anti-PD-1, anti-PD-L1, and anti-OX-40 agonistic antibody, led to a prolonged survival of mice in preclinical studies, suggesting the therapeutic potential of the PD-1/PD-L1 pathway for high-risk osteosarcoma [40].
However, clinical studies of ICIs have failed to produce satisfactory results in osteosarcoma. Phase I study of ipilimumab in pediatric patients with advanced or relapsed solid tumors including eight osteosarcomas failed to show clinical benefit as a single agent, despite observing an increase in activated HLA-DR(+) Ki67(+) T cells without concomitant upregulating Tregs among the patients [42]. A recent phase II clinical trial of anti-PD1 pembrolizumab for advanced sarcomas reported that 7 out of 40 patients with soft tissue sarcoma (18%) and only 2 out of 40 patients (5%) with bone sarcomas had objective responses [43]. The study included twenty-two patients with osteosarcoma; one patient (5%) had a partial response, six patients (27%) had a stable disease, and fifteen patients (68%) showed disease progression. Another study of pembrolizumab in advanced osteosarcoma also failed to show clinical benefit despite high PD-L1 expression in tumors (11 of 12 patients): median progression-free survival (PFS) was 1.7 months and median overall survival (OS) was 6.6 months [44]. A clinical trial of the PD-L1 inhibitor (avelumab) for recurrent or progressive osteosarcoma was no more successful, where 17 out of the 18 treated patients showed disease progression while on study (NCT03006848). The low clinical activity of single PD-1 or PD-L1 blockade in most sarcoma subtypes suggests that PD-1 or PD-L1 inhibitor alone cannot adequately revive exhausted or tolerized effector T cells in these patients. These results contrast with undifferentiated pleomorphic sarcomas showing good clinical response accompanied by high numbers of TILs [43], emphasizing the need to develop strategies to enhance T cell infiltration. Although the combination of two ICIs acting through different mechanisms, such as anti-CTLA4 and anti-PD-1, has shown synergy in preclinical models of osteosarcoma as well as in those of melanoma [40][45], such combinations have had mixed response so far in bone sarcomas. A combination of nivolumab and ipilimumab failed to show efficacy in patients with osteosarcoma [46], and a combination of durvalumab (anti-PD-1) and tremelimumab (anti-CTLA4) resulted in two partial responses out of five osteosarcoma patients treated [47]. Several cases reported that the combination of anti-CTLA4 and anti-PD-1 antibodies induced remission and tumor stabilization in patients with metastatic osteosarcoma [48][49], while the addition of camrelizumab (anti-PD-1 inhibitor) to the inhibition of vascular endothelial growth factor receptor 2 (VEGFR2)] using apatinib (tyrosine kinase inhibitor (TKI)) was shown to prolong PFS of patients with advanced osteosarcoma compared with apatinib alone [50]. The overall findings suggest that a combination strategy rather than a stand-alone therapy may be the path to the future.

3. Adoptive T Cell Immunotherapy for Osteosarcoma

While ICIs are nonspecific, adoptive T cell immunotherapy (ATC) using CAR or BsAb is tumor-antigen-specific, directly driving T cells to the tumors and inducing potent cytotoxicity. CAR and BsAb are engineered to recognize tumor-associated antigens (TAAs) and exert T cell-mediated cytotoxicity in a major histocompatibility complex (MHC)-independent manner. Although CAR T cells achieved extraordinary clinical success in hematologic malignancies receiving FDA approvals, they exhibit generally inconsistent and non-durable effects on solid cancers due to tumoral heterogeneity, physical barrier, aberrant vasculature, and the immunosuppressive TME [51][52][53][54]. Anti-tumor efficacy of ATC primarily derives from recognition by VH (variable region of heavy chain) and VL (variable region of light chain) of target antigen-specific antibodies. Ideal TAAs carry epitopes exclusively expressed on tumor cell surface to allow engineered antibodies or receptors to drive T cells selectively into tumors while minimizing off-tumor toxicities. To avoid tumor escape, TAA should be ideally expressed homogenously within and between tumors among patients. The targets reported so far for ATC in osteosarcoma include HER2, GD2, B7-H3 (CD276), interleukin-11 receptor α-chain (IL-11Rα), insulin-like growth factor 1 receptor (IGF1R), receptor tyrosine kinase-like orphan receptor 1 (ROR1), erythropoietin-producing hepatocellular class A2 (EphA2), natural killer group 2D ligand (NKG2DL), activated leukocyte cell adhesion molecule (ALCAM, CD166), folate receptor-α (FRα), chondroitin sulfate proteoglycan 4 (CSPG4), and CD151 [55][56][57]. Among them, HER2, GD2, and B7H3 have been studied the most for osteosarcoma [58][59][60][61][62][63].
Although osteosarcoma cell lines and tissue sections were HER2-positive by immunohistochemistry or flow cytometry [11][58], HER2 gene amplification was rarely observed in osteosarcoma, and the expression levels were much lower than those of HER2(+) breast cancers [64], accounting for the clinical insensitivity of OS to trastuzumab [8]. Despite its HER2 antigen density being too low for conventional IgG-mediated cytotoxicity, osteosarcoma was effectively killed by HER2-CAR T cells, which, when injected intratumorally, induced the regression of established osteosarcoma xenografts, prolonging survival of the mice [11]. HER2-CAR T cells also decreased the sarcosphere forming capacity and bone tumor generating ability, suggesting the potential to target osteosarcoma stem cells [61]. A phase I/II study of HER2-CAR T cells without lymphodepletion resulted in a stable disease in 3 and progressed disease in 12 among 16 patients with recurrent/refractory HER2(+) osteosarcoma (NCT00902044). Although these results were modest, HER2-CAR T cells could traffic to tumor sites and persist for more than 6 weeks in a dose-dependent manner [60]. In the same trial, five osteosarcomas, three rhabdomyosarcomas, one Ewing sarcoma, and one synovial sarcoma were treated with HER2-CAR T cells following lymphodepletion. Among them, three had a stable disease, five had a progressive disease, while one rhabdomyosarcoma and one osteosarcoma patient had complete remission for 12 months and 32 months, respectively [65].
GD2, another promising target for CAR and BsAb, is overexpressed in many cancers including osteosarcoma while being limited in normal tissues [58][66][67]. GD2 has a role in signal transduction and cell adhesion, and overexpression of GD2 increases the phosphorylation of paxillin and focal adhesion kinase (FAK), promoting migration and invasion of osteosarcoma cells [68]. The third-generation GD2-CAR T cells using anti-GD2 clone 14G2a successfully recognized GD2(+) sarcoma cell lines and showed cytotoxicity in vitro, but the accumulation of myeloid-derived suppressor cells (MDSCs) attenuated the anti-tumor effect of GD2-CAR T cells in vivo [69]. This inhibition phenomenon was observed in a clinical trial of GD2-CAR T cells in neuroblastoma: GD2-CAR T cells with or without lymphodepletion resulted in modest antitumor responses, with a striking expansion of CD45/CD33/CD11b/CD163 (+) myeloid cells in all patients [70]. The fourth-generation GD2-CAR T cells using the hu3F8 clone can also effectively target osteosarcoma cells and induce PD-L1 on tumor cells and PD-1 on GD2-CAR T cells, limiting T cell activity. Combination with low-dose doxorubicin decreased PD-L1, enhancing the potency of GD2-CAR T cells on osteosarcoma in vitro [62]. Recently, Del Bufalo et al. reported exceptional results of GD2-CAR T cells in patients with relapsed or refractory neuroblastoma. Twenty-seven patients were treated with third-generation GD2-CAR T cells, and the overall response was 63%; nine patients had a complete response, eight had a partial response; toxicities were tolerable, and the inducible caspase 9 suicide gene was needed only in one patient (GD2-CART01) [71]. Another third-generation GD2-CAR T cells combined with a safety switch (GD2-CAR.OX40.28.z.ICD9) are being tested for solid tumors including osteosarcoma in a phase I clinical trial (NCT02107963).
B7-H3 (CD276) CAR T cells are also being tested for the treatment of osteosarcoma. B7-H3 is a checkpoint molecule expressed at high levels on pediatric solid tumors including osteosarcoma [72][73], and it contributes to tumor immune evasion and metastasis, correlating with poor prognosis [74]. B7-H3-targeting CAR T cells have shown anti-tumor activity in osteosarcoma xenograft models [63][75]. A phase I clinical trial is currently recruiting patients with solid tumors that express B7-H3 (NCT04483778).
On the other hand, T-BsAb represents another promising alternative which effectively drives T cells to the tumor sites with less toxicity. T-BsAbs are also mostly known for their use in hematological malignancies similarly to CAR T cells, and blinatumomab (a CD3 × CD19 BsAb built on scFv framework) was FDA approved in 2014 and has been successful against relapsed or refractory acute lymphoblastic leukemia (ALL) [76][77]. For solid tumors, catumaxomab (CD3xEpCAM BsAb) targeting epithelial cell adhesion molecule (EpCAM)-positive cancers showed benefit in reducing malignant ascites secondary to epithelial cancers, with an acceptable safety profile [78][79][80]. To improve efficacy and to reduce clinical toxicities, BsAb-armed T cells, using chemically conjugated BsAb, anti-GD2 × anti-CD3 [hu3F8 × mouse OKT3 (NCT02173093)], anti-HER2 × anti-CD3 [trastuzumab × mouse OKT3 (NCT00027807)], or anti-EGFR × anti-CD3 [cetuximab × mouse OKT3 (NCT04137536)], were developed and tested in clinical studies, proven effective and safe in breast, neuroblastoma, prostate, and pancreatic cancers [81][82][83][84]. GD2-BsAb-armed T cells were tested for their efficacy on GD2-positive tumors and induced a significant PET response in one out of three osteosarcoma patients (NCT02173093) [85]. To harness the potential of BsAb against solid tumors, the BsAb structural format was found to be critical [86][87]. Despite similar in vitro anti-tumor properties of GD2-BsAb formats, including monomeric BiTE, dimeric BiTE, IgG heterodimer, IgG-[H]-scFv, or chemical conjugate, the IgG-[L]-scFv format, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor binding IgG, proved the most effective in vivo, driving more T cells into tumors and producing more durable anti-tumor responses [87]. For osteosarcoma cell lines that are HER2-positive and/or GD2-positive, IgG-[L]-scFv GD2-BsAb (hu3F8 × huOKT3) or HER2-BsAb (trastuzumab × huOKT3) administered intravenously successfully drove T cells into tumors to exert potent cytotoxicity in vivo [58]. T cells armed ex vivo (EAT) with the IgG-[L]-scFv-formatted GD2-BsAb (GD2-EATs) or HER2-BsAb (HER2-EATs) also successfully ablated both osteosarcoma cell-line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) with significantly lower cytokine release while increasing the overall survival [58][87]. Although a phase I/II study of this IgG-[L]-scFv-formatted GD2-BsAb (Nivatrotamab) in patients with relapsed/refractory neuroblastoma, osteosarcoma, and other GD2(+) solid tumors was temporarily suspended because of company business priorities (NCT03860207), clinical results are anticipated. 

References

  1. Luetke, A.; Meyers, P.A.; Lewis, I.; Juergens, H. Osteosarcoma treatment—Where do we stand? A state of the art review. Cancer Treat. Rev. 2014, 40, 523–532.
  2. Longhi, A.; Ferrari, S.; Tamburini, A.; Luksch, R.; Fagioli, F.; Bacci, G.; Ferrari, C. Late effects of chemotherapy and radiotherapy in osteosarcoma and Ewing sarcoma patients: The Italian Sarcoma Group Experience (1983–2006). Cancer 2012, 118, 5050–5059.
  3. Isakoff, M.S.; Bielack, S.S.; Meltzer, P.; Gorlick, R. Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. J. Clin. Oncol. 2015, 33, 3029–3035.
  4. Coley, W.B. The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 1910, 3, 1–48.
  5. Muller, C.R.; Smeland, S.; Bauer, H.C.; Saeter, G.; Strander, H. Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: Long term results of the Karolinska Hospital series. Acta Oncol. 2005, 44, 475–480.
  6. Meyers, P.A.; Schwartz, C.L.; Krailo, M.D.; Healey, J.H.; Bernstein, M.L.; Betcher, D.; Ferguson, W.S.; Gebhardt, M.C.; Goorin, A.M.; Harris, M.; et al. Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival—A report from the Children’s Oncology Group. J. Clin. Oncol. 2008, 26, 633–638.
  7. Bielack, S.S.; Smeland, S.; Whelan, J.S.; Marina, N.; Jovic, G.; Hook, J.M.; Krailo, M.D.; Gebhardt, M.; Papai, Z.; Meyer, J.; et al. Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b versus MAP Alone in Patients with Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial. J. Clin. Oncol. 2015, 33, 2279–2287.
  8. Ebb, D.; Meyers, P.; Grier, H.; Bernstein, M.; Gorlick, R.; Lipshultz, S.E.; Krailo, M.; Devidas, M.; Barkauskas, D.A.; Siegal, G.P.; et al. Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: A report from the children’s oncology group. J. Clin. Oncol. 2012, 30, 2545–2551.
  9. Ha, H.T.; Griffith, K.A.; Zalupski, M.M.; Schuetze, S.M.; Thomas, D.G.; Lucas, D.R.; Baker, L.H.; Chugh, R. Phase II trial of cetuximab in patients with metastatic or locally advanced soft tissue or bone sarcoma. Am. J. Clin. Oncol. 2013, 36, 77–82.
  10. Kopp, L.M.; Malempati, S.; Krailo, M.; Gao, Y.; Buxton, A.; Weigel, B.J.; Hawthorne, T.; Crowley, E.; Moscow, J.A.; Reid, J.M.; et al. Phase II trial of the glycoprotein non-metastatic B-targeted antibody-drug conjugate, glembatumumab vedotin (CDX-011), in recurrent osteosarcoma AOST1521: A report from the Children’s Oncology Group. Eur. J. Cancer 2019, 121, 177–183.
  11. Ahmed, N.; Salsman, V.S.; Yvon, E.; Louis, C.U.; Perlaky, L.; Wels, W.S.; Dishop, M.K.; Kleinerman, E.E.; Pule, M.; Rooney, C.M.; et al. Immunotherapy for osteosarcoma: Genetic modification of T cells overcomes low levels of tumor antigen expression. Mol. Ther. 2009, 17, 1779–1787.
  12. Yu, A.L.; Uttenreuther-Fischer, M.M.; Huang, C.S.; Tsui, C.C.; Gillies, S.D.; Reisfeld, R.A.; Kung, F.H. Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J. Clin. Oncol. 1998, 16, 2169–2180.
  13. Edelman, M.; Dvorkin, M.; Laktionov, K.K.; Navarro, A.; Juan-Vidal, O.; Kozlov, V.; Golden, G.; Jordan, O.; Deng, C. The anti-disialoganglioside (GD2) antibody dinutuximab (D) for second-line treatment (2LT) of patients (pts) with relapsed/refractory small cell lung cancer (RR SCLC): Results from part II of the open-label, randomized, phase II/III distinct study. J. Clin. Oncol. 2020, 38, 9017.
  14. Modi, S.; Jacot, W.; Yamashita, T.; Sohn, J.; Vidal, M.; Tokunaga, E.; Tsurutani, J.; Ueno, N.T.; Prat, A.; Chae, Y.S.; et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N. Engl. J. Med. 2022, 387, 9–20.
  15. Reed, D.R.; Janeway, K.A.; Minard, C.G.; Hall, D.; Crompton, B.D.; Lazar, A.J.; Wang, W.-L.; Voss, S.D.; Militano, O.; Gorlick, R.G.; et al. PEPN1924, a phase 2 study of trastuzumab deruxtecan (DS-8201a, T-DXd) in adolescents and young adults with recurrent HER2+ osteosarcoma: A children’s oncology group pediatric early-phase clinical Trial Network study. J. Clin. Oncol. 2023, 41, 11527.
  16. Barber, D.L.; Wherry, E.J.; Masopust, D.; Zhu, B.; Allison, J.P.; Sharpe, A.H.; Freeman, G.J.; Ahmed, R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006, 439, 682–687.
  17. Trautmann, L.; Janbazian, L.; Chomont, N.; Said, E.A.; Gimmig, S.; Bessette, B.; Boulassel, M.R.; Delwart, E.; Sepulveda, H.; Balderas, R.S.; et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 2006, 12, 1198–1202.
  18. Day, C.L.; Kaufmann, D.E.; Kiepiela, P.; Brown, J.A.; Moodley, E.S.; Reddy, S.; Mackey, E.W.; Miller, J.D.; Leslie, A.J.; DePierres, C.; et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006, 443, 350–354.
  19. Urbani, S.; Amadei, B.; Tola, D.; Massari, M.; Schivazappa, S.; Missale, G.; Ferrari, C. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol. 2006, 80, 11398–11403.
  20. Dong, H.; Strome, S.E.; Salomao, D.R.; Tamura, H.; Hirano, F.; Flies, D.B.; Roche, P.C.; Lu, J.; Zhu, G.; Tamada, K.; et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat. Med. 2002, 8, 793–800.
  21. Schumacher, T.N.; Schreiber, R.D. Neoantigens in cancer immunotherapy. Science 2015, 348, 69–74.
  22. Schumacher, T.N.; Scheper, W.; Kvistborg, P. Cancer Neoantigens. Annu. Rev. Immunol. 2019, 37, 173–200.
  23. Hacohen, N.; Fritsch, E.F.; Carter, T.A.; Lander, E.S.; Wu, C.J. Getting personal with neoantigen-based therapeutic cancer vaccines. Cancer Immunol. Res. 2013, 1, 11–15.
  24. Champiat, S.; Ferte, C.; Lebel-Binay, S.; Eggermont, A.; Soria, J.C. Exomics and immunogenics: Bridging mutational load and immune checkpoints efficacy. Oncoimmunology 2014, 3, e27817.
  25. Mouw, K.W.; Goldberg, M.S.; Konstantinopoulos, P.A.; D’Andrea, A.D. DNA Damage and Repair Biomarkers of Immunotherapy Response. Cancer Discov. 2017, 7, 675–693.
  26. Takahashi, T.; Tagami, T.; Yamazaki, S.; Uede, T.; Shimizu, J.; Sakaguchi, N.; Mak, T.W.; Sakaguchi, S. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 2000, 192, 303–310.
  27. Rowshanravan, B.; Halliday, N.; Sansom, D.M. CTLA-4: A moving target in immunotherapy. Blood 2018, 131, 58–67.
  28. Callahan, M.K.; Postow, M.A.; Wolchok, J.D. CTLA-4 and PD-1 Pathway Blockade: Combinations in the Clinic. Front. Oncol. 2014, 4, 385.
  29. Park, J.A.; Cheung, N.V. Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies. Cancer Treat. Rev. 2017, 58, 22–33.
  30. Leach, D.R.; Krummel, M.F.; Allison, J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996, 271, 1734–1736.
  31. Palmerini, E.; Agostinelli, C.; Picci, P.; Pileri, S.; Marafioti, T.; Lollini, P.L.; Scotlandi, K.; Longhi, A.; Benassi, M.S.; Ferrari, S. Tumoral immune-infiltrate (IF), PD-L1 expression and role of CD8/TIA-1 lymphocytes in localized osteosarcoma patients treated within protocol ISG-OS1. Oncotarget 2017, 8, 111836–111846.
  32. Yoshida, K.; Okamoto, M.; Sasaki, J.; Kuroda, C.; Ishida, H.; Ueda, K.; Okano, S.; Ideta, H.; Kamanaka, T.; Sobajima, A.; et al. Clinical outcome of osteosarcoma and its correlation with programmed death-ligand 1 and T cell activation markers. OncoTargets Ther. 2019, 12, 2513–2518.
  33. Gao, W.; Zhou, J.; Ji, B. Evidence of Interleukin 21 Reduction in Osteosarcoma Patients Due to PD-1/PD-L1-Mediated Suppression of Follicular Helper T Cell Functionality. DNA Cell Biol. 2017, 36, 794–800.
  34. Zhang, M.L.; Chen, L.; Li, Y.J.; Kong, D.L. PD-L1/PD-1 axis serves an important role in natural killer cell-induced cytotoxicity in osteosarcoma. Oncol. Rep. 2019, 42, 2049–2056.
  35. Koirala, P.; Roth, M.E.; Gill, J.; Piperdi, S.; Chinai, J.M.; Geller, D.S.; Hoang, B.H.; Park, A.; Fremed, M.A.; Zang, X.; et al. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci. Rep. 2016, 6, 30093.
  36. Huang, X.; Zhang, W.; Zhang, Z.; Shi, D.; Wu, F.; Zhong, B.; Shao, Z. Prognostic Value of Programmed Cell Death 1 Ligand-1 (PD-L1) or PD-1 Expression in Patients with Osteosarcoma: A Meta-Analysis. J. Cancer 2018, 9, 2525–2531.
  37. Shen, J.K.; Cote, G.M.; Choy, E.; Yang, P.; Harmon, D.; Schwab, J.; Nielsen, G.P.; Chebib, I.; Ferrone, S.; Wang, X.; et al. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol. Res. 2014, 2, 690–698.
  38. Liao, Y.; Chen, L.; Feng, Y.; Shen, J.; Gao, Y.; Cote, G.; Choy, E.; Harmon, D.; Mankin, H.; Hornicek, F.; et al. Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells. Oncotarget 2017, 8, 30276–30287.
  39. Lussier, D.M.; O’Neill, L.; Nieves, L.M.; McAfee, M.S.; Holechek, S.A.; Collins, A.W.; Dickman, P.; Jacobsen, J.; Hingorani, P.; Blattman, J.N. Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions. J. Immunother. 2015, 38, 96–106.
  40. Shimizu, T.; Fuchimoto, Y.; Fukuda, K.; Okita, H.; Kitagawa, Y.; Kuroda, T. The effect of immune checkpoint inhibitors on lung metastases of osteosarcoma. J. Pediatr. Surg. 2017, 52, 2047–2050.
  41. Zheng, B.; Ren, T.; Huang, Y.; Sun, K.; Wang, S.; Bao, X.; Liu, K.; Guo, W. PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse. J. Hematol. Oncol. 2018, 11, 16.
  42. Merchant, M.S.; Wright, M.; Baird, K.; Wexler, L.H.; Rodriguez-Galindo, C.; Bernstein, D.; Delbrook, C.; Lodish, M.; Bishop, R.; Wolchok, J.D.; et al. Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. Clin. Cancer Res. 2016, 22, 1364–1370.
  43. Tawbi, H.A.; Burgess, M.; Bolejack, V.; Van Tine, B.A.; Schuetze, S.M.; Hu, J.; D’Angelo, S.; Attia, S.; Riedel, R.F.; Priebat, D.A.; et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017, 18, 1493–1501.
  44. Boye, K.; Longhi, A.; Guren, T.; Lorenz, S.; Naess, S.; Pierini, M.; Taksdal, I.; Lobmaier, I.; Cesari, M.; Paioli, A.; et al. Pembrolizumab in advanced osteosarcoma: Results of a single-arm, open-label, phase 2 trial. Cancer Immunol. Immunother. 2021, 70, 2617–2624.
  45. Lussier, D.M.; Johnson, J.L.; Hingorani, P.; Blattman, J.N. Combination immunotherapy with alpha-CTLA-4 and alpha-PD-L1 antibody blockade prevents immune escape and leads to complete control of metastatic osteosarcoma. J. Immunother. Cancer 2015, 3, 21.
  46. D’Angelo, S.P.; Mahoney, M.R.; Van Tine, B.A.; Atkins, J.; Milhem, M.M.; Jahagirdar, B.N.; Antonescu, C.R.; Horvath, E.; Tap, W.D.; Schwartz, G.K.; et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): Two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018, 19, 416–426.
  47. Somaiah, N.; Conley, A.P.; Parra, E.R.; Lin, H.; Amini, B.; Solis Soto, L.; Salazar, R.; Barreto, C.; Chen, H.; Gite, S.; et al. Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: A single-centre phase 2 trial. Lancet Oncol. 2022, 23, 1156–1166.
  48. Sterz, U.; Grube, M.; Herr, W.; Menhart, K.; Wendl, C.; Vogelhuber, M. Case Report: Dual Checkpoint Inhibition in Advanced Metastatic Osteosarcoma Results in Remission of All Tumor Manifestations-A Report of a Stunning Success in a 37-Year-Old Patient. Front. Oncol. 2021, 11, 684733.
  49. Nuytemans, L.; Sys, G.; Creytens, D.; Lapeire, L. NGS-analysis to the rescue: Dual checkpoint inhibition in metastatic osteosarcoma—A case report and review of the literature. Acta Clin. Belg. 2021, 76, 162–167.
  50. Xie, L.; Xu, J.; Sun, X.; Guo, W.; Gu, J.; Liu, K.; Zheng, B.; Ren, T.; Huang, Y.; Tang, X.; et al. Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: A single-arm, open-label, phase 2 trial. J. Immunother. Cancer 2020, 8, e000798.
  51. Beatty, G.L.; O’Hara, M. Chimeric antigen receptor-modified T cells for the treatment of solid tumors: Defining the challenges and next steps. Pharmacol. Ther. 2016, 166, 30–39.
  52. Gajewski, T.F. Failure at the effector phase: Immune barriers at the level of the melanoma tumor microenvironment. Clin. Cancer Res. 2007, 13, 5256–5261.
  53. Moon, E.K.; Wang, L.C.; Dolfi, D.V.; Wilson, C.B.; Ranganathan, R.; Sun, J.; Kapoor, V.; Scholler, J.; Pure, E.; Milone, M.C.; et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin. Cancer Res. 2014, 20, 4262–4273.
  54. Gust, J.; Hay, K.A.; Hanafi, L.A.; Li, D.; Myerson, D.; Gonzalez-Cuyar, L.F.; Yeung, C.; Liles, W.C.; Wurfel, M.; Lopez, J.A.; et al. Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer Discov. 2017, 7, 1404–1419.
  55. Lin, Z.; Wu, Z.; Luo, W. Chimeric Antigen Receptor T-Cell Therapy: The Light of Day for Osteosarcoma. Cancers 2021, 13, 4469.
  56. Zhu, J.; Simayi, N.; Wan, R.; Huang, W. CAR T targets and microenvironmental barriers of osteosarcoma. Cytotherapy 2022, 24, 567–576.
  57. Wang, H.; Jin, X.; Zhang, Y.; Wang, Z.; Zhang, T.; Xu, J.; Shen, J.; Zan, P.; Sun, M.; Wang, C.; et al. Inhibition of sphingolipid metabolism in osteosarcoma protects against CD151-mediated tumorigenicity. Cell Biosci. 2022, 12, 169.
  58. Park, J.A.; Cheung, N.V. GD2 or HER2 targeting T cell engaging bispecific antibodies to treat osteosarcoma. J. Hematol. Oncol. 2020, 13, 172.
  59. Koksal, H.; Muller, E.; Inderberg, E.M.; Bruland, O.; Walchli, S. Treating osteosarcoma with CAR T cells. Scand. J. Immunol. 2019, 89, e12741.
  60. Ahmed, N.; Brawley, V.S.; Hegde, M.; Robertson, C.; Ghazi, A.; Gerken, C.; Liu, E.; Dakhova, O.; Ashoori, A.; Corder, A.; et al. Human Epidermal Growth Factor Receptor 2 (HER2)-Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J. Clin. Oncol. 2015, 33, 1688–1696.
  61. Rainusso, N.; Brawley, V.S.; Ghazi, A.; Hicks, M.J.; Gottschalk, S.; Rosen, J.M.; Ahmed, N. Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Cancer Gene Ther. 2012, 19, 212–217.
  62. Chulanetra, M.; Morchang, A.; Sayour, E.; Eldjerou, L.; Milner, R.; Lagmay, J.; Cascio, M.; Stover, B.; Slayton, W.; Chaicumpa, W.; et al. GD2 chimeric antigen receptor modified T cells in synergy with sub-toxic level of doxorubicin targeting osteosarcomas. Am. J. Cancer Res. 2020, 10, 674–687.
  63. Majzner, R.G.; Theruvath, J.L.; Nellan, A.; Heitzeneder, S.; Cui, Y.; Mount, C.W.; Rietberg, S.P.; Linde, M.H.; Xu, P.; Rota, C.; et al. CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity against Pediatric Solid Tumors and Brain Tumors. Clin. Cancer Res. 2019, 25, 2560–2574.
  64. Somers, G.R.; Ho, M.; Zielenska, M.; Squire, J.A.; Thorner, P.S. HER2 amplification and overexpression is not present in pediatric osteosarcoma: A tissue microarray study. Pediatr. Dev. Pathol. 2005, 8, 525–532.
  65. Navai, S.A.; Derenzo, C.; Joseph, S.; Sanber, K.; Byrd, T.; Zhang, H.M.; Mata, M.; Gerken, C.; Shree, A.; Mathew, P.R.; et al. Administration of HER2-CAR T cells after lymphodepletion safely improves T cell expansion and induces clinical responses in patients with advanced sarcomas. Cancer Res. 2019, 79, LB-147.
  66. Roth, M.; Linkowski, M.; Tarim, J.; Piperdi, S.; Sowers, R.; Geller, D.; Gill, J.; Gorlick, R. Ganglioside GD2 as a therapeutic target for antibody-mediated therapy in patients with osteosarcoma. Cancer 2014, 120, 548–554.
  67. Poon, V.I.; Roth, M.; Piperdi, S.; Geller, D.; Gill, J.; Rudzinski, E.R.; Hawkins, D.S.; Gorlick, R. Ganglioside GD2 expression is maintained upon recurrence in patients with osteosarcoma. Clin. Sarcoma Res. 2015, 5, 4.
  68. Shibuya, H.; Hamamura, K.; Hotta, H.; Matsumoto, Y.; Nishida, Y.; Hattori, H.; Furukawa, K.; Ueda, M.; Furukawa, K. Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3. Cancer Sci. 2012, 103, 1656–1664.
  69. Long, A.H.; Highfill, S.L.; Cui, Y.; Smith, J.P.; Walker, A.J.; Ramakrishna, S.; El-Etriby, R.; Galli, S.; Tsokos, M.G.; Orentas, R.J.; et al. Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas. Cancer Immunol. Res. 2016, 4, 869–880.
  70. Heczey, A.; Louis, C.U.; Savoldo, B.; Dakhova, O.; Durett, A.; Grilley, B.; Liu, H.; Wu, M.F.; Mei, Z.; Gee, A.; et al. CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Mol. Ther. 2017, 25, 2214–2224.
  71. Del Bufalo, F.; De Angelis, B.; Caruana, I.; Del Baldo, G.; De Ioris, M.A.; Serra, A.; Mastronuzzi, A.; Cefalo, M.G.; Pagliara, D.; Amicucci, M.; et al. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N. Engl. J. Med. 2023, 388, 1284–1295.
  72. Wang, L.; Zhang, Q.; Chen, W.; Shan, B.; Ding, Y.; Zhang, G.; Cao, N.; Liu, L.; Zhang, Y. B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS ONE 2013, 8, e70689.
  73. Modak, S.; Kramer, K.; Gultekin, S.H.; Guo, H.F.; Cheung, N.K. Monoclonal antibody 8H9 targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors. Cancer Res. 2001, 61, 4048–4054.
  74. Picarda, E.; Ohaegbulam, K.C.; Zang, X. Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy. Clin. Cancer Res. 2016, 22, 3425–3431.
  75. Hidalgo, L.; Somovilla-Crespo, B.; Garcia-Rodriguez, P.; Morales-Molina, A.; Rodriguez-Milla, M.A.; Garcia-Castro, J. Switchable CAR T cell strategy against osteosarcoma. Cancer Immunol. Immunother. 2023, 72, 2623–2633.
  76. Przepiorka, D.; Ko, C.W.; Deisseroth, A.; Yancey, C.L.; Candau-Chacon, R.; Chiu, H.J.; Gehrke, B.J.; Gomez-Broughton, C.; Kane, R.C.; Kirshner, S.; et al. FDA Approval: Blinatumomab. Clin. Cancer Res. 2015, 21, 4035–4039.
  77. Kantarjian, H.; Stein, A.; Gokbuget, N.; Fielding, A.K.; Schuh, A.C.; Ribera, J.M.; Wei, A.; Dombret, H.; Foa, R.; Bassan, R.; et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N. Engl. J. Med. 2017, 376, 836–847.
  78. Heiss, M.M.; Murawa, P.; Koralewski, P.; Kutarska, E.; Kolesnik, O.O.; Ivanchenko, V.V.; Dudnichenko, A.S.; Aleknaviciene, B.; Razbadauskas, A.; Gore, M.; et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int. J. Cancer 2010, 127, 2209–2221.
  79. Knodler, M.; Korfer, J.; Kunzmann, V.; Trojan, J.; Daum, S.; Schenk, M.; Kullmann, F.; Schroll, S.; Behringer, D.; Stahl, M.; et al. Randomised phase II trial to investigate catumaxomab (anti-EpCAM × anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer. Br. J. Cancer 2018, 119, 296–302.
  80. Burges, A.; Wimberger, P.; Kumper, C.; Gorbounova, V.; Sommer, H.; Schmalfeldt, B.; Pfisterer, J.; Lichinitser, M.; Makhson, A.; Moiseyenko, V.; et al. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM × anti-CD3 antibody: A phase I/II study. Clin. Cancer Res. 2007, 13, 3899–3905.
  81. Lum, L.G.; Thakur, A.; Al-Kadhimi, Z.; Colvin, G.A.; Cummings, F.J.; Legare, R.D.; Dizon, D.S.; Kouttab, N.; Maizel, A.; Colaiace, W.; et al. Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. Clin. Cancer Res. 2015, 21, 2305–2314.
  82. Yankelevich, M.; Kondadasula, S.V.; Thakur, A.; Buck, S.; Cheung, N.K.; Lum, L.G. Anti-CD3 × anti-GD2 bispecific antibody redirects T-cell cytolytic activity to neuroblastoma targets. Pediatr. Blood Cancer 2012, 59, 1198–1205.
  83. Reusch, U.; Sundaram, M.; Davol, P.A.; Olson, S.D.; Davis, J.B.; Demel, K.; Nissim, J.; Rathore, R.; Liu, P.Y.; Lum, L.G. Anti-CD3 × anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model. Clin. Cancer Res. 2006, 12, 183–190.
  84. Vaishampayan, U.; Thakur, A.; Rathore, R.; Kouttab, N.; Lum, L.G. Phase I Study of Anti-CD3 × Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. Prostate Cancer 2015, 2015, 285193.
  85. Yankelevich, M.; Modak, S.; Chu, R.; Lee, D.W.; Thakur, A.; Cheung, N.-K.V.; Lum, L.G. Phase I study of OKT3 × hu3F8 bispecific antibody (GD2Bi) armed T cells (GD2BATs) in GD2-positive tumors. J. Clin. Oncol. 2019, 37 (Suppl. S15), 2533.
  86. Santich, B.H.; Park, J.A.; Tran, H.; Guo, H.F.; Huse, M.; Cheung, N.V. Interdomain spacing and spatial configuration drive the potency of IgG--scFv T cell bispecific antibodies. Sci. Transl. Med. 2020, 12, eaax1315.
  87. Park, J.A.; Santich, B.H.; Xu, H.; Lum, L.G.; Cheung, N.V. Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release. J. Immunother. Cancer 2021, 9, e002222.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Jeong A Park
,
Nai-Kong V. Cheung
View Times: 129
Revisions: 2 times (View History)
Update Date: 28 Aug 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback