== Schematic representation of various BsAb formats

== Schematic representation of various BsAb formats. is usually a leading cause of death worldwide. The global cancer burden, which has been estimated as 18.1 million new cases and 9.6 million deaths in 2018, is predicted to rise to 29.5 million new incidences in 2040 [1,2]. The alarming increase in cancer burden accentuates the urgent need to develop innovative approaches for more effective and less toxic cancer treatments complementing BMP10 conventional therapeutics such as chemotherapy, radiotherapy, surgery and palliative care. Cancer immunotherapy holds great promises in cancer treatment, which was named as the Breakthrough of the Year in 2013 byScience[3]. Tumor associated carbohydrate antigens (TACAs) are a class of attractive antigens for anti-cancer immunotherapy development [4,5]. Multiple TACAs are over-expressed on the surface of cancer Tenosal cells compared to those on normal cells [6]. In addition, TACAs can be found at high levels on many types of cancer, rendering them intriguing targets for potential broad spectrum anti-cancer immunotherapy [7]. Tremendous efforts have been devoted to the development of anti-cancer vaccines targeting TACAs with innovative designs of the antigen structures, the carrier moieties to deliver the antigens to the immune system, as well as incorporation of immune activation elements including adjuvants and cytotoxic T cell epitopes into the vaccine constructs [811]. Besides vaccines, chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs) have emerged as appealing immunotherapeutic strategies to combat malignancy, as evident from multiple products approved by the FDA [12]. Recently, great progresses have been achieved in the development of CAR T cells and BsAbs targeting two TACAs, i.e., gangliosides GD2 and glycoprotein mucin-1 (MUC1). In this review, we will discuss the advances and challenges in these areas to stimulate further development. == 2. GD2 CAR T cells: going beyond the anti-GD2 monoclonal antibodies == Disialoganglioside GD2 is usually anN-acetyl neuraminic acid made up of glycolipid antigen composed of five monosaccharides anchored to the lipid bilayer of plasma membrane through a ceramide lipid (Physique 1). Normal tissues have low expression levels of GD2 [13], but in various types of cancers such as neuroblastoma, small-cell lung cancer, melanoma, glioma, and sarcomas, the expression of this weakly immunogenic antigen can reach 107molecules per cell [8,14,15]. Furthermore, GD2 has been discovered as a potential biomarker for the purported breast malignancy stem cells [16]. GD2 can induce tyrosine phosphorylation leading to activation of a variety of kinase pathways, resulting in increased proliferation, cell migration and invasion of cancer cells. Knockdown of GD2 levels abrogated tumor formationin vivo[16]. With its high expression on tumor cells and importance in tumor development, GD2 was ranked as one of the top antigenic targets for cancer [14,17]. == Physique 1. == Structure of the GD2 ganglioside. Monoclonal antibodies against GD2 have achieved clinical success in cancer treatment. Early generation of anti-GD2 cancer immunotherapy utilized murine monoclonal antibodies, 14G2a and 3F8, in patients with melanoma, neuroblastoma, and osteosarcoma [14]. However, due to the mouse origin of these antibodies, significant human anti-mouse antibodies were induced, limiting the dose that can be administered and reducing their anti-tumor efficacy. In addition, administration of these antibodies are associated with side effects such as pain, fever, hypertension and urticarial reactions, which Tenosal limit their wide applications. To overcome these challenges, human-mouse chimeric anti-GD2 monoclonal antibodies have been generated [14,18]. ch14.18 consisting of the variable regions of murine 14G2a Tenosal mAb fused with the constant regions of human IgG1, has higher antibody-dependent cell-mediated cytotoxicity and longer half-life compared to 14G2a. Further development of humanized anti GD2 antibody, hu3F8 and hu14.18K322A with a K322A mutation of the Fc region to prevent complement fixation, improved their half-lives and tolerable dose. However, in clinical trials, similar side effects as m3F8, including pain and hypertension, were observed. Adoptive transfer of CAR T cells is usually a promising immunotherapy Tenosal strategy to treat cancer.