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Matsumoto, Y.; Ju, T. Tumor-Associated Carbohydrate Antigen-Targeted Immunotherapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/46832 (accessed on 22 June 2024).
Matsumoto Y, Ju T. Tumor-Associated Carbohydrate Antigen-Targeted Immunotherapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/46832. Accessed June 22, 2024.
Matsumoto, Yasuyuki, Tongzhong Ju. "Tumor-Associated Carbohydrate Antigen-Targeted Immunotherapy" Encyclopedia, https://encyclopedia.pub/entry/46832 (accessed June 22, 2024).
Matsumoto, Y., & Ju, T. (2023, July 14). Tumor-Associated Carbohydrate Antigen-Targeted Immunotherapy. In Encyclopedia. https://encyclopedia.pub/entry/46832
Matsumoto, Yasuyuki and Tongzhong Ju. "Tumor-Associated Carbohydrate Antigen-Targeted Immunotherapy." Encyclopedia. Web. 14 July, 2023.
Tumor-Associated Carbohydrate Antigen-Targeted Immunotherapy
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Glycosylation is one of the most pivotal post-translational modifications on all types of biomolecules for the formation of glycoproteins, glycolipids, and glycoRNAs in a tissue-type specific manner. Normal glycans participate in biological events such as development, metabolism, differentiation, and immunity in mammalian cells. In cancers, the altered glycosylation, known as tumor-associated carbohydrate antigens (TACAs), is specifically expressed on cell surface molecules and play important roles in facilitating tumor formation, progression, metastasis, and immunosurveillance evasion by generating the vulnerable tumor microenvironment through the interaction of glycan binding receptors expressed on immune cells. TACAs are potential tumor glyco-biomarkers, glycoimmune checkpoints, and therapeutics.

glycosylation glycans glycoproteins tumor-associated carbohydrate antigens (TACAs) cancer immunotherapy immunocheckpoint

1. Tn and STn Antigens as Pan-Carcinoma TACAs

Among highly relevant TACAs, the Tn antigen (GalNAcα1-O-Ser/Thr/Tyr) and its sialylated version of the Tn antigen (STn, Neu5Acα2-6GalNAcα1-O-Ser/Thr) are widely expressed in a majority of human carcinomas originated from gastrointestines, pancreas, lung, breast, prostate, bladder, and ovary [1][2]. Tn and STn antigens, categorized as pan-carcinoma antigens, are truncated O-GalNAc or mucin-type O-glycans and associated with poor prognosis and cancer progression such as early carcinogenesis, progression, metastasis by suppression of immunosurveillance [3][4][5][6][7][8][9][10][11]. In addition to their expression on the plasma membrane of tumor cells, a variety of Tn/STn-carrying glycoproteins, such as mucins, CA 15-3 (MUC1), CA 125 (MUC16), and CA 72-4 (MUC1), are secreted in circulation in patients with gynecologic cancer [12][13][14][15][16][17][18], digestive cancer [19], gastric cancer [20][21], pancreatic cancer [22], and endometrial cancer [23], and the titers of those serum glycoproteins correlate with cancer malignancies [24][25]. Thus, they have been developed as diagnostic biomarkers in a cancer type-specific manner. While those diagnostics are evaluated with specific mAbs that generally recognize both carbohydrates and surrounding peptides, it would be quite challenging to generate mAbs against such shortened glycan epitopes, particularly the Tn antigen, which monosaccharide, α-linked GalNAc is less immunogenic and may not be processed by MHC-II T cell-dependent immune response [26][27][28]. Another complexity is that anti-Tn mAbs may cross-react with α-linked GalNAc-terminating structures, such as blood group A (BGA) and Forssman-related antigens [29][30], resulting in false positivity in serum diagnosis. Additionally, human IgA1 in circulation carries the Tn antigen in its hinge region [31][32][33], which may also interfere with the diagnostic specificity. Nevertheless, specific anti-Tn mAbs are widely under investigation as valuable tools for cancer diagnosis and therapeutics.
Approximately 30 different anti-Tn/STn mAbs have been developed and reported [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63], and several mAbs show the therapeutic potential in preclinical study [37][46][47][48][50][60][61][63][64][65][66][67][68].
Interestingly, elevated titers of anti-Tn/STn antibodies were observed in sera from patients with gastrointestinal cancer [69], prostate cancer [70], and breast cancer [71]. Although those antibodies are also found in healthy donors at some levels due to infections of microorganisms and parasites [72][73][74][75][76], elevation of those antibodies would be good indicators of diagnosis/prognosis in cancers. Tn and STn antigens are not solely biomarkers, they play roles in immune tolerance and anti-inflammatory response in which macrophage galactose-type lectin (MGL, also known as CLEC10A) on macrophages and dendric cells (DCs) binds to the Tn antigen, facilitating the generation of hostile tumor microenvironment (TME) within and even around tumor tissues (Figure 1) [77][78][79][80][81][82][83][84]. Furthermore, the STn antigens on mucins overexpressed in cancer cells create an immunosuppressive environment in which sialic acid-binding immunoglobulin (Ig)-like lectins (i.e., SIGLECs) on most of innate immune cells and NK cells bind to the STn antigen, leading to immunosuppression and evasion of immunosurveillance (Figure 1) [85][86][87][88][89][90]. Studies also showed that Tn and STn antigens trigger epithelial-mesenchymal transition (EMT), invasion, metastasis, and immune surveillance [91][92][93]. Therefore, vaccination with the Tn/STn antigens-carrying immunogens has been proposed and studied in clinical trials.
Figure 1. Contributions of Tn, STn antigens, and GD2 to the tumor microenvironment (TME). The Tn antigen binds to macrophage galactose-type lectin (MGL) on macrophages and dendric cells, leading to secreted anti-inflammatory cytokines, and induced angiogenesis. Sialic acid-binding immunoglobulin (Ig)-like lectins (SIGLECs) on innate immune cells and NK cells binds to sialic acids in the STn antigen and GD2 on cancer cells, inducing immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated inflammatory cascades to facilitate the TME.
Notably, a recombinant chimeric anti-Tn human IgG1 mAb, Remab6, was generated by the de novo sequencing of a murine anti-Tn IgM mAb, CA3638 (BaGs6), which was originally generated by an immunization of mouse with Tn+ erythrocytes from patients with Tn syndrome [43][55]. The anti-Tn IgM mAb (CA3638) was shown to be specific to the Tn antigen in human cancer cell lines [94], human carcinoma tissue sections [95], mouse tissues with c1galt1c1 (COSMC) gene knockout [96][97][98][99][100][101], or c1galt1 (T-synthase) gene knockout [102]. The epitope requirement was determined to be two consecutive Tn antigens or two Tn antigens in a conformationally proximity regardless of the peptide sequences [103]. The Remab6 showed high specificity to human carcinomas including gastrointestinal, breast, prostate, ovarian, pancreatic tissues of tumor origin, but not normal tissues [55][104]. In therapeutic point of view, the core fucosylation of N-glycans at N297 in the CH2 domain on human IgG negatively regulates antibody-dependent cellular cytotoxicity (ADCC) by interfering with IgG-Fc receptor interaction on effector cells [105][106][107]. The glycoengineered version of Remab6, named Remab6-AF (aFucosylated), showed a potent ADCC to Tn+ human tumor cells in both in vitro and in vivo settings [68]. Importantly, several anti-Tn/STn mAbs mostly bind Tn/STn-carrying mucins, which would not induce complement-dependent cytotoxicity (CDC) activity in many cases [108]. Remab6, however, can target multiple Tn+ glycoproteins other than mucins, and share some Tn+ glycoproteins that are recognized by MGL receptor [109], suggesting that it would overcome one of the big hurdles of immunotherapy targeting the Tn antigen and the TME in human carcinomas.
In summary, although some of anti-Tn mAbs are not highly specific to the Tn antigens (GalNAc-α1-O-S/T/Y) often expressed on tumor cells, they can still be valuable for cancer diagnosis if proper controls are included. Furthermore, the anti-Tn immunotherapies hold great potentials since targeting the Tn antigens is not solely attacking the tumor cells but also activating local immune cells to overcome the TME.

2. CA 19-9 in Pancreatic and Digestive Carcinomas

CA 19-9, terms sialyl Lewis A (SLeA), is one of the most classic TACAs and clinically used as a diagnostic serum biomarker for detecting pancreatic carcinoma over four decades [110][111]. Magnani et al. initially described the putative structure of SLeA as a glycolipid of monosialoganglioside using a monoclonal antibody immunized with a human colorectal carcinoma cell line, SW1116 [112][113]. Later on, the epitopes of SLeA were also found on both N- and O-glycans on mostly mucins, and apolipoproteins in sera of gastrointestinal and pancreatic carcinoma patients [114][115][116]. It has been shown that SLeA, in general, contributes to vessel invasion and extravasation-mediated platelets and leukocyte attachment to endovascular tissues [117][118][119][120][121][122]. CA 19-9 is elevated in sera of patients with gastrointestinal and pancreatic cancers [19][21][123][124][125][126][127][128][129]. However, a series of studies demonstrates that diagnostic test with CA 19-9 may not be specific for those cancer patients since CA 19-9 levels in sera are also found to be elevated in patients with pancreatitis, cirrhosis, and biliary obstruction, causing a false positivity in many cases [112][130][131]. The other study demonstrates that SLeX, which is an isomer of SLeA, is elevated in sera of patients with pancreatic cancer that are SLeA-negative [132]. Currently, CA 19-9 is only used for detecting pancreatic cancer and monitoring in the course of treatment of patients with gastrointestinal carcinomas [133][134].
Several mAbs to CA 19-9 have been developed and evaluated in detecting pancreatic carcinomas [135]. Characterization of those mAbs on glycan arrays revealed that some mAbs show a broad specificity beyond SLeA, which causes cross-reactivity with sialyl Lewis C (SLeC, also known as DU-PAN-2) that lacks fucose on SLeA [136][137]. Of note, the individuals who do not express α1,3-Fucosyltransferase-3 (FucT-3) that is a responsible enzyme to form Lewis A structure, known as Lewis-negative, even suffered from pancreatic cancer [135][138][139]. Approximately, 20% of Caucasian and African American populations are Lewis-negative due to genotypic variants and lower activity of FucT-3 [138], which led to the false negative diagnosis of CA 19-9 in patients [133][140]. A few studies demonstrated the elevation of serum levels of SLeC in Lewis-negative patients with pancreatic cancer [139], and also showed that serum levels of SLeC was higher than CA 19-9 in patients with digestive cancer [141].

3. GD2 in Neuroblastoma and Glioma

GD2 is an intermediate member of acidic glycosphingolipids (GSLs) overexpressed in melanoma, glioma, neuroblastoma, and small cell lung cancer (SCLC) [117][142][143][144][145][146][147]. The expression of GD2 is barely seen in normal tissues, except in brain and skin with weak expression levels, as GD2 is an intermediate product in the ganglioside biosynthesis [148]. Some GSLs act as immune-suppressors and harness oncogenic signaling pathways upon clustering membrane-bound molecules in microdomains to induce cell growth, adhesion, and invasive activity in melanoma, neuroblastoma, glioma, SCLC, and osteosarcoma [142][143][149][150][151][152][153][154][155][156][157][158][159][160]. A recent study suggests that GD2 interacts with SIGLEC7 on innate immune cells to suppress local immunity, thus promoting tumor cell evasion from immunosurveillance (Figure 1) [161][162]. Therefore, GD2 is recognized as TACAs for a variety of solid tumors and a target for cancer therapy [163].
Several mAbs targeting GD2 have been developed and showed anti-tumoral effects with CDC and ADCC against neuroblastoma and lymphoma in vitro and in vivo [164][165][166][167][168][169]. Other than antibody-mediated cytotoxicity to cancers, one of the anti-GD2 mAbs, 220-51, exhibited suppression of cell growth and induction of anoikis in SCLC in vitro [170][171].
Dinutuximab (UnituxinTM [172]), a chimeric human anti-GD2 mAb, was approved by the FDA for treatment of patients with high-risk neuroblastoma in 2015 (NCT00026312) [173][174]. Dinutuximab is originally derived from 14.18 mouse hybridoma and expressed in SP2/0 cells by the Reisfeld group [165]. Recent studies reported that Dinutuximab-treated patients with neuroblastoma relapsed due to an adrenergic-to-mesenchymal transition (AMT), leading to low expression levels of GD2 [175]. It was found that treatment with EZH2 inhibitor (Tazemetostat, an FDA-approved drug to follicular lymphoma, NCT01897571) blocks AMT and induces re-expression of GD2 in neuroblastoma, suggesting that combination treatment of two drugs would be clinically beneficial for children with high-risk neuroblastoma [175]. In another study, Dinutuximab was reported to suppress cell growth in GD2+ cell lines of neuroblastoma, osteosarcoma, and SCLC and block an immunosuppressive axis of GD2-SIGLEC7 in macrophages, enhancing phagocytotic activity with no obvious neurotoxic side-effects in an in vivo mouse model [161]. These phagocytotic effects are significantly synergized with co-treatment of anti-CD47 mAb (Magrolimab) that inhibits SIRPα-mediated ‘don’t eat me’ signaling in macrophages. A combination of those two therapeutic drugs (Dinutuximab/Magrolimab) is now being tested in patients with relapsed or refractory neuroblastoma or relapsed osteosarcoma in Phase I trial (NCT04751383). In other anti-GD2 immunotherapeutic strategies, a fusion protein with a humanized version of anti-GD2 mAb (hu14.18)-linked to human interleukin 2 (IL2) (EMD273063) was developed and tested for patients with GD2+ tumors such as neuroblastoma and melanoma in Phase I/II trials (NCT00590824, and NCT00082758) [176][177][178][179]. Dinutuximab beta is the dinutuximab manufactured in Chinese hamster ovary (CHO) cell line, was developed and approved in Europe, and is currently in clinical trials in the US (NCT05558280, NCT05272371, NCT04253015, and NCT05080790). Currently, a combination of Dinutuximab beta and intravenous IL2 administration is also being tested for high-risk neuroblastoma patients in Phase III trial (NCT01704716) [180].
Naxitamab is another humanized therapeutic anti-GD2 mAb (hu3F8) originally derived from 3F8 mouse hybridoma [164]. The combination of Naxitamab with GM-CSF immunotherapy was approved by the FDA in 2020 for patients with relapsed or refractory neuroblastoma (NCT03363373, and NCT01757626) [181][182][183]. Furthermore, a bispecific antibody (BsAb) targeting GD2 and CD3 (Nivatrotamab, hu3F8 x huOKT3 BsAb [184]) has entered in Phase I/II trials for patients with metastatic SCLC, neuroblastoma, and osteosarcoma (NCT03860207, and NCT04750239). The trials were terminated due to business priorities.

4. Targeting Neoantigens in Carcinomas

A class of most well-known neoantigens is mucins (i.e., MUC1, MUC16), which is observed in both membrane-bound and secretory forms in patients originated from gastrointestines, breast, pancreas, and ovary [185][186][187]. CA 15-3 (MUC1) and CA 125 (MUC16) are serum biomarkers for patients with breast, lung, pancreas, ovarian, and prostate cancers [188][189][190], and their titers and glycoforms were evaluated in several diagnostic studies (See more details in Section 1). Studies showed that those oncogenic mucins are highly expressed and heavily glycosylated with shortened/truncated O-glycans such as Tn/STn antigens in a proline/threonine/serine-rich tandem repeat domain (PTS domain), thus can serve as novel therapeutic targets [187][191][192][193]. Of note, the secreted forms of those mucins, particularly MUC1, can suppress T cell proliferation and interfere with T cell activation (Figure 2a) [194][195][196].
Figure 2. Anti-Mucin therapeutic approaches to human carcinomas. (a) Tumor-associated MUC1 (CA 15-3) expressed on cancer cells, or secreted from cancer cells (arrows), suppresses T cell proliferation and activation (dashed arrows). (b) A schematic illustration of approaches in anti-MUC16 therapy based on 4H11 that recognizes an ectodomain (ED) next to a site of shedding of MUC16 (CA 125), targeting to cancer cells (arrow in red). CART, chimeric antigen receptor T-cell, inducing CD8+ cytotoxicity; BiTEs, bispecific T-cell engagers (anti-MUC16 x anti-CD3 scFvs), recruiting and directly activating T cells to induce cellular immune response.
The first generation of mAbs targeting MUC1 includes SM3, HMFG1/2 (formerly known as 1.10.F3/3.14.A3) [197][198][199], and AR20.5 [200]. SM3 recognizes both glycosylated and unglycosylated forms of MUC1 [201], and HMFG1 also shows a similar binding activity to both glycosylated and unglycosylated MUC1 [202]. However, AR20.5 has a striking binding to Tn+MUC1 glycopeptide over unglycosylated MUC1 peptide and exhibits CDC/ADCC activity in vitro [203]. Another feature of AR20.5 is to form immune complexes with circulating MUC1 and/or MUC1-expressing tumor cells in vivo, implying that it may stimulate a dendric cell-mediated T cell response [204]. Recently, those SM3 and AR20.5-based immunotherapies in conjugation with immunotoxin (mAb-conjugated with Granulysis, GRNLY) have been tested in Tn+ cancer cell lines including a pancreatic cell line, Capan-2, and a leukemic cell line, Jurkat, in both in vitro and in vivo mouse models, and resulted in targeted lysis of tumors with Tn+MUC1 [205]. Another novel mAb targeting MUC1 is PankoMab-GEX, which is a well-defined mAb from screening with a synthetic Tn+ glycopeptides [206]. Its humanized and glycoengineered version, Gatipotuzumab, was tested in patients with Tn+MUC1 positive tumors in Phase I and II trials, and showed well-tolerance with common adverse events (NCT01222624, and NCT01899599) [207][208]. One promising CART therapy targeting Tn+MUC1 was developed by the Posey group in 2016 [209], validating the concept of immunotherapy with SM3 and HMFG2 since early 2000s [210]. Consequently, HMFG2-, and SM3-scFv have been applied in the latest platform of CART technologies (HMFG2 in a third generation of CART [211]; SM3 in a PD-1 knockout CART), and they are currently being tested in clinical trials (NCT03198052, and NCT03525782, respectively).
In targeting MUC16 (Figure 2b), one of the well-characterized mAbs is 4H11 that recognizes the epitope within the retained MUC16 ectodomain next to shedding domain [212]. The MUC16-CART was developed by the Brentjens group in 2010 [213]. Later, they developed other versions of MUC16-CART with additional modifications, such as 4H11-scFv-fused with IL12, or fused with PD-1 blocking scFv, which have shown a robust anti-tumoral activity to ovarian cancer cell line in preclinical studies [214][215]. In next-generation immunotherapy, anti-MUC16 scFv (4H11-scFv) was employed on a bispecific T-cell engagers (BiTEs), which displayed redirected T-cell immunologic synapses and suppressed metastatic potential of epithelial ovarian cancer in an in vivo mouse model [216]. In enhancing anti-tumoral efficacy of MUC16-BiTEs, co-treatment with VEGF or PD-1 blocking antibodies significantly decreased tumor burden in an in vivo mouse model, suggesting that combination treatment with those blocking antibodies would be more beneficial to patients with ovarian cancer under the immunosuppressive TME. DMUC5754A, an ADC that contains a humanized anti-MUC16 with MMAE, was developed and tested in patients with ovarian and pancreatic cancers in Phase I trial, showing that DMUC5754A has anti-tumor activity in MUC16+ patients with an acceptable safety profile (NCT01335958) [217]. This humanized anti-MUC16 mAb was originally derived from mouse hybridoma clone 3A5 that targets multiple sites on mucin repeat of a shedding form of MUC16 [218]. Lastly, Oregovomab (originally from B43.13 [219][220]) was tested in patients with ovarian cancer in Phase II trial (NCT01616303), resulting in an improved overall survival with induced CA125-specific T cell production [221][222] and is currently being tested in Phase III trial (NCT04498117).
Other than mucins, glycoproteins CEA (carcinoembryonic antigen, also known as CEACAM5 [223]) and PSA (prostate-specific antigen [224]) are classic serum biomarkers in a majority of carcinomas [12][19][20][125][126][225][226][227][228][229]. CEA is a GPI-anchored glycoprotein overexpressed in solid adenocarcinomas of lung, colon, intestine, stomach, pancreas, liver and cervix, and the expression levels are associated with cell adhesion, differentiation, lymph node metastasis, and poor prognosis [223][230]. Like CA 19-9, CEA has also been used in cancer screening over the decades. However, CEA levels are also reported to be elevated in non-malignancies such as peptic ulcer disease, inflammatory bowel disease (IBD), and pancreatitis. Thereby, CEA is currently only used in monitoring disease course and prognosis after surgical resection as recommended in the guidelines [231][232][233]. Nevertheless, ADC version of a humanized anti-CEACAM5 mAb (SAR408377)-conjugated with maytansinoid agent DM4 has been evaluated in a preclinical setting and is currently being tested in patients with non-small lung cancer in several clinical trials (NCT04524689, NCT4394624, and NCT02187848) [234]. The other anti-CEACAM5-based drug, ADC version of labetuzumab govitecan-conjugated with SN-38 (IMMU-130, originally from MN-14 [235][236][237]) has been tested in patients with refractory or relapsed metastatic colorectal cancer in Phase I/II trial and demonstrated a manageable safety profile and therapeutic activity (NCT01270698) [238]. A Phase II study (NCT01915472) of IMMU-130 in patients with metastatic colorectal cancer was proposed and withdrawn since no patients were enrolled in any studies.
PSA is a glycoprotein exclusively secreted by prostate carcinomas over benign prostate tissues [224][239]. From a diagnostic point of view, PSA is very sensitive, and the early diagnosis with PSA test shows >50% reduction of mortality with 95% confidence and decreased the incidence of metastasis in 55 to 75-year-old men when a routine screening test was performed [240][241]. It is the single most useful tool for the early detection of prostate cancers. While its diagnostic value is highly appreciated, little has been reported in PSA-targeted therapeutics. Nevertheless, PROSTVAC, PSA-based vaccine immunotherapy-stimulating DC-T cell axis, is underway in combination therapies such as Nivolumab (anti-PD-1 mAb), or CV301 (CEA-MUC1-TRICOM vaccine) + MSB0011359C (M7824, anti-PD-L1 x anti-TGF-β receptor II BsAb) in patients with metastatic castration-resistant prostate cancer (mCRPC) in several clinical trials (NCT029333255, NCT03315871, NCT01145508, and NCT02649855) [242][243].

5. Immunotherapies Involving in Glycobiology and Glycoimmunology

As altered glycosylation on cell surface and secretary proteins is prominent in a majority of human carcinomas, TACA-targeted immunotherapy offers new opportunities for treatment of cancers. While next-generation immunotherapies have been introduced to overcome cancers such as CART, bispecific antibody, or vaccination that directly activate T-cell dependent immune response, anti-TACA immunotherapy has entered in several clinical trials, as discussed in above sections. Also, TACAs play some role in facilitating the TME in glycan-lectin receptor interaction with immune cells [244][245][246]. Therefore, the Bertozzi group has developed a new conceptual antibody-enzyme drug, bi-sialidase fusion protein (E-602), which is trastuzumab (anti-HER2 mAb)-conjugated with neuraminidase that cleaves sialic acids on HER2+ cancer cells, resulting in an enhanced ADCC activity and immune cell activation upon desialylation in the TME in local tumor site in preclinical studies (Figure 3) [247][248]. E-602 is currently being tested for dose escalation and dose expansion in Phase I/II trial (NCT05259696). In another example, VISTA (V-domain immunoglobulin suppressor of T cell activation, also known as B7-H5) was found to act as a binding partner to the adhesion and co-inhibitory receptor of PSGL-1 (P-selectin glycoprotein ligand-1, expressed on T cells [249][250]) at an acidic environment. At the TME, the interaction of VISTA with PSGL-1 was engaged in T cell suppression [251]. A co-treatment with a blockage against VISTA and anti-PD-1 mAb reversed immune suppressive effects in vivo [251][252]. Interestingly, the binding of VISTA requires sulfated tyrosine and protonated histidine residue on PSGL-1 on T cells, but not SLeX that is required for the binding to P-selectin in tethering and infiltration into inflamed tissues, implying that the blockage to VISTA would not interfere with PSGL-1-P-selectin-mediated immunological activity. In addition, several types of GBRs are being investigated and under development as immune modulatory targets (Figure 3): E-selectin (Phase I/II, NCT02306291, and Phase III, NCT03616470 [253][254]), SIGLECs (SIGLEC2 (CD22), NCT01564784 [255]; SIGLEC3 (CD33), NCT00927498, approved by the FDA [256]; SIGLEC15, NCT03665285 [257]), Galectins (Galectin-1, NCT01724320; Galectin-3, NCT02117362, and NCT02575404 [258][259]), NKG2 family in preclinical studies [260][261][262], and DC-SIGN in preclinical study [263]. Thus, a series of data supports that anti-TACA therapy could potentially act as a glycoimmune checkpoint to block immunosuppressive synapses and remodel the TME in local tumor sites.
Figure 3. Summary of strategic approaches of anti-TACA immunotherapy herein. (a) TACA vaccine therapy: Fine-tuning glyco-vaccine design is the key to anti-TACA vaccination. Optimizely designed glycopeptide vaccines are endocytosed, processed by antigen presenting cells (APCs), and antigenic “glyco”epitopes are presented on T cells to induce cellular immune responses (activation of CD8+ cytotoxic T cells, and IgG class switch in B cells) (arrows). Vaccinations with TACAs or glycopeptides should be designed not to stimulate glycan-binding receptors (GBRs) such as MGL and SIGLECs on immune cells which forge the TME (dashed arrows). Particularly, MUC1 glycopeptide vaccines with potential effects of T cell suppression should be avoided (see also Figure 2a). (b) Glycan-receptor therapy: Glycan-lectin receptor axis creates the hostile immunosuppressive TME. Blocking the binding of certain TACAs such as the Tn antigen, and sialic acid-containing glycans to their receptors, MGL and SIGLECs (arrows), could be a promising approach as a glycoimmune checkpoint (TACA-GBR axis) (dashed arrows). Bi-sialidase (E-602, trastuzumab-conjugated with sialidase) is a novel therapeutic approach to suppress the TME in local site. (c) Anti-TACA therapy—Consideration of the TACA targets: Although specific anti-TACA mAbs with high affinity are critical, choice of TACA targets for immunotherapy needs to be seriously considered. The potential hurdles for anti-MUC immunotherapies could arise from secreted and shedding MUCs in circulation, which might sequester CART and mAbs from tumor cells to compromise their anti-tumor activity. Furthermore, anti-MUC mAbs that target to membrane-bound mucins do not show CDC activity. Ideally, anti-MUC therapy would be targeting to MUCs that remain on cancer cell surface (see also Figure 2b). Taking that consideration, anti-Tn/STn immunotherapies targeting Tn/STn-carrying glycoproteins other than soluble MUCs may offer better options (arrows in red). *mAb includes ADC, glycoengineered version, BiTEs, and bsAb.
Disclaimer: The views expressed in this text are those of the authors and do not necessarily reflect the official policy or position of the United States Food and Drug Administration and the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.

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