TACA : specific therapeutic cancer biomarkers ?
While browsing through posters or reading scientific articles related to oncology, you probably came across the term "TACA".
But what does the acronym TACA refer to ? And why is it mentioned so often?
Let’s put an end to suspense. TACA means Tumor-associated carbohydrate antigens.
Tumor-associated carbohydrate antigens can be divided into two main classes :
- glycoprotein antigens including Tn (Thomsen nouveau), Thomsen−Friendreich (TF), and sialyl-Tn (sTn) linked to the hydroxyl group of serine or threonine residues of protein;
- glycolipid antigens, which are carbohydrates linked to ceramide lipids and anchored to the lipid bilayer on the cell surface through hydrophobic interactions. The glycolipids can be further classified into several families:
- the gangliosides such as GD2, GD3, GM2, GM3, and fucosyl-GM1;
- globo class such as Globo-H, Gb3, Gb4, and Gb5;
- blood group determinants such as LewisX (SSEA-1), LewisY, and their sialylated derivates (Sle).
Tumor-associated carbohydrate antigens are molecular markers aberrantly expressed on human tumor cells, which can be used to distinguish cancer cells from normal tissues. Since TACAs are barely expressed on normal tissues due to their tumor specificity, they are particularly interesting markers to target in the development of cancer immunotherapy strategies.
Tumor-associated carbohydrate antigens play an important role in tumor cells and help define various behaviors and pathways, including apoptosis, motility, alteration of the transmembrane receptor tyrosine kinase pathway, angiogenesis, and adhesion through cadherins, integrins, selectins, or siglecs, among others.
Three major increased expression or altered presence remain associated with cancer diagnosis:
- truncated glycans (STn, Tn, T)
- branching of N-glycans
- sialic acid containing glycans.
TACA-based cancer vaccine approach : a promising active immunotherapy strategy facing many drawbacks
Historically, the first approach to targeting altered sugars was through the development of therapeutic vaccines. Despite the strenuous efforts of many scientific teams, this strategy has so far systematically failed over the years due to numerous obstacles.
Availability and preparation of a sufficient quantity of sugars with a high level of purity as immunogen
When performing immunizations, it is necessary that the immunogen used is as pure as possible or it may trigger undirected responses. In the case of sugars, the problem is complicated by the fact that you risk obtaining a certain heterogeneity of composition of the sugars during the preparation which will induce a non-specific immune response for the target. Nevertheless, glycobiology techniques have improved significantly in recent years and it is now possible to correctly separate closely related sugars from a fungal culture.
Carbohydrate antigens are T-cell-independent
Unlike peptides and proteins, sugars are not degraded by the proteasome and presented by the major histocompatibility complex. Inducing only the activation of B cells, you therefore risk the induction of a secretion of IgM that is not very specific for your target without ever obtaining long-term immune protection. To convert the immunity type to IgG-type, cells need to interact with Th-cells.
Low immunogenicity of carbohydrate antigens
By nature, sugars, like lipids, are self molecules and therefore haptens. This means that they induce a weak immune response and that they often need to be adjoined with carrier proteins (e.g. Theratope® STn-KLH vaccine from Biomira) and powerful adjuvants able to break the immunotolerance (e.g. QS21 for pentavalent Globo vaccine from Memorial Sloan Kettering Cancer Center).
The current TACA vaccine pipeline is mainly dominated by the Memorial Sloan Kettering Cancer Center (MSKCC) entity:
- The Theratope® (STn) vaccine applied in metastatic breast cancer designation failed to bring clinical benefits in phase 3 study despite its early success.
- MSKCC's Globo-H-GM2-sTn-TF-Tn pentavalent vaccine has demonstrated good safety and immunogenicity results in Phase I.
- MSKCC has licensed OBI-822 Globo-H vaccine to Obi Pharma and concluded Phase II in 2020.
- GD2-GD3 bivalent vaccine is co-developed by MSKCC and Y-mAbs Therapeutics and currently being tested in neuroblastoma patients Phase II.
- In February 2022, Odeon Therapeutics Inc. has acquired rights to two cancer candidates from Obi Pharma in a deal worth up to $200 million including therapeutic cancer vaccine OBI-833.
TACA-based therapeutic antibody approach : a new passive immunotherapy hope for cancer treatment?
Although significant progress has been made in the treatment of cancer with TACA, no vaccines have been approved at this time, primarily because it remains far too difficult to elicit a protective T cell-mediated immune response against saccharide antigens. In response to these recurring failures of sugar-based vaccine approaches, various companies and scientists have shifted their focus to the use of monoclonal antibodies and their derivatives: bispecifics, Antibody-Drug Conjugates (ADCs) and Chimeric antigen receptor T cells (CAR-Ts).
Naked monoclonal antibody therapy to cancer cell associated carbohydrates
The generation of antibodies against carbohydrate targets presents the same challenges as those related to TACA vaccine efficacy: if ever successful, the monoclonal antibodies generated are generally low affinity, low specificity and IgM isotype.
In the case of SYnAbs, we systematically manage to generate IgG antibodies with high affinity and no cross-reactivity to sugar analogues. But this is another story that we would be more than happy to discuss outside of this article. And remember that other companies have also succeeded :
- Kyowa Hakko Kogyo with Ecromeximab, a chimeric antibody targeting GD3, but with insufficient efficacy and finally discontinued
- ReceptaBio, with RebmAb100 and RebmAb300 which recognize respectively the Lewis antigen of blood group Y (LeY) and Lewis of blood group B (LeB) in patients with ovarian and breast tumors, but with insufficient efficacy in phase II trials
- National Cancer Institute with MVT-5873, a cytotoxic monoclonal antibody targeting carbohydrate antigen 19-9 (CA 19-9) or Sialyl Lewis(a) in patients undergoing resections pancreatic cancer, cholangiocarcinoma or metastatic colorectal cancer to the liver
- APEIRON Biologics with approved Dinutuximab, a chimeric IgG1 monoclonal antibody that reacts specifically with the carbohydrate moieties of disialoganglioside 2 (GD2), which is highly expressed on the surface of neuroblastoma cells.
Despite multiple developments of monoclonal antibodies targeting tumor-related sugars, it does not seem that an antibody alone can be sufficient to be truly effective on tumor cells, and many antibodies have seen their life end in the clinic due to insufficient efficacy despite a good toxicity profile. This is why new approaches have emerged, especially ADCs on TACA targets.
Antibody-Drug Conjugate therapeutic approach to Tumor-associated carbohydrate antigens
Several ADCs are currently being developed from naked antibodies that have previously failed in the clinic. This is the case of :
- SGN15 from Seagen, developped from BR96 monoclonal antibody (internalizing antibody that binds to Lewis Y (Le(y)) conjugated to doxorubicin and docetaxel
- SGN-STNV from Seagen, thanks to the acquisition of Siamab Therapeutics and its anti-STn monoclonal antibody
- DS3939 from Daiichi Sankyo’s, developed from PankoMab-GEX or Gatipotuzumab (initially developed by Glycotope) a glyco-optimised humanised IgG1, with high affinity to tumour-specific glycopeptide epitope of MUC1 (TA-MUC1)
- PF-06688992 from Pfizer, developed from MSKCC anti- ganglioside GD3 monoclonal antibody and now discontinued after Phase I on melanoma patients.
CAR immunotherapy approach to sugar antigens in oncology treatments
CAR cells are designed by linking the single-chain variable fragment (scFv) of a monoclonal antibody with the cell receptor of an immune cell. The mentioned cell can be a T lymphocyte (CAR-T), a Natural Killer cell (CAR-NK), a Natural Killer T cell (CAR-NKT), and even a macrophage (CAR-M).
Regarding TACA targets for CAR adoptive transfer approach, the first and most abundantly targeted antigen remains disialoganglioside GD2, an N-acetyl neuraminic acid containing glycolipid antigen composed of five monosaccharides anchored to the lipid bilayer of plasma membrane through a ceramide lipid.
For the different entities currently active in the field, we can mention:
- CureSearch, with a GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas
- Baylor College of Medicine, with GD2-CAR NKT and Interleukin-15 to treat children with Neuroblastoma
Nevertheless, other glycan targets are also investigated:
- TAG 72, glycoprotein truncated sialyl-Tn (Cartherics, a dual CAR T)
- A range of tumor-associated antigens MUC1 glycoforms, including MUC1 Tn, STn, T, and ST, as well as unglycosylated MUC1 (Experimental Cancer Medicine Centre at King’s College London and NIHR with a panel of eight engineered CARs using scFvs derived from SM3 and HMFG2 antibodies)
- Lewis Y (Monash University, Peter MacCallum Cancer Centre…with CAR T)
Given that ADC therapy may present the inconvenience of efflux pump-induced drug resistance (EPMDR), that autologous CARs approach remain to date an expensive treatment involving a sufficient number of T cells to be reinjected (complicated in patients with lymphopenia) and that allogeneic CARs may induce GvHD and CRS effects, judicious choice of a bispecific immunotherapeutic could be a possible solution.
Bispecific antibodies (BsAbs) targeting Tumor-Associated Glycans
Bispecifics have the particularity of possessing two paratopes and therefore of recognizing two different epitopes, allowing the bringing together of cancer cells and immune cells, and thus maximizing the therapeutic effects of immunotherapies.
Ektomab/TRBs07 (Trion Pharma), recognizes ganglioside GD2 and CD3 on human T cells. Interestingly, comparison of GD2 BsAbs and CAR T cells revealed that BsAbs resulted in longer survival of activated T cells (S.S. Hoseini et al, 2017).
Similarly, different bispecific to MUC1 have been developed (MUC1-CD16, MUC1-CD3, MUC1-CD28…) and are currently in clinical investigation (Benhealth Biopharmaceutical,…).
Conclusion on Tumor-Associated Carbohydrate Antigens therapies
While active vaccine immunotherapy on TACA targets seems to have shown its limits in the past, passive approaches based on antibodies such as bispecifics and CARs are giving new hope. However, a third way forward could be the combination of TACA-based vaccines with checkpoint inhibitors, CTLA-4 and PD-1 blocking antibodies.