Trastuzumab derived HER2-specific CARs for the treatment of trastuzumab-resistant breast cancer: CAR T cells penetrate and eradicate tumors that are not accessible to antibodies

HER2-targeted monoclonal antibodies improve the outcome for advanced breast cancer patients; however, resistance to therapy is still frequent. Epitope masking and steric hindrance to antibody binding through matrix components are thought to be the major mechanism. We asked whether tumors resistant to trastuzumab can still be eliminated by CAR T cells redirected by the same antibody domain. While saturating doses of trastuzumab in the presence of CD16.176V.NK-92 effector cells and trastuzumab derived CAR T cells equally well recognized and killed HER2-positive tumor cells in a monolayer, only CAR T cells penetrated into the core region of tumor spheroids and exhibited cytotoxic activity in vitro, whereas antibodies failed. In NSG mice treatment with trastuzumab and CD16.176V.NK-92 cells only transiently retarded tumor growth but did not induce regression of clinically trastuzumab-resistant breast cancer xenografts. In contrast, one dose of HER2-specific CAR T cells eradicated established tumors resulting in long-term survival. Data indicate that CAR T cells can successfully combat antibody resistant tumors by targeting the same epitope suggesting that CAR T cells can penetrate the tumor matrix which is a barrier for antibodies

Genetic regulation of delayed-type hypersensitivity responses to poly(LTyr, LGlu)-poly(DLAia)--poly(LLys). I, Expression of the genetic defect at two phases of the immune process.J. Exp. Med

Immune responses to the synthetic polypeptide poly(LTyr,LGlu)-poly(DLAla)-poly(LLys) [(T,G)-A--L] 1 (1), such as humoral responses (2), delayed-type hypersensitivity responses (DTH) (3), and antigen-dependent T-cell proliferation, (4) are regulated by genes that are located in the major histocompatibility complex of the mouse (H-2). Thus, mice possessing the H-2 b haplotype are responders and mice of the H-2 a'ax'k'8 haplotypes are nonresponders. In a previous study (3), we have demonstrated the existence of two types of nonresponder mouse strains: (a) H-2 a and H-2 k haplotypes; educated T cells of these strains could mediate DTH responses to (T,G)-A--L in the appropriate (responder × nonresponder)F1 mice but not in syngeneic recipients, and (b) H-2 t and H-2 s haplotypes; T cells of these strains could not be activated to mediate DTH responses in any recipient. These studies suggested that the defect in DTH responses to (T,G)-A--L in H-2 ~ and H-2 k mice is not expressed on their T cells or on their antigen-presenting cells in the activation phase. In this study we have analyzed the efferent phase of the DTH response to (T,G)-A--L to identify the cell type which expresses the genetic defect. Here we hav

CAR's made it to the pancreas

Despite intensive treatment, pancreatic adenocarcinoma still has the worst prognosis among all malignancies. Using clinically relevant models, we demonstrated the therapeutic efficacy of adoptively transferred T cells engineered with a carcinoembryonic antigen (CEA) and ERBB2-specific chimeric antigen receptor against pancreatic carcinoma. Targeting CD24, a putative cancer stem cell antigen expressed by a minority of carcinoma cells, was likewise effective

X-ray structures of a hydrolytic antibody and of complexes elucidate catalytic pathway from substrate binding and transition state stabilization through water attack and product release

The x-ray structures of the unliganded esterase-like catalytic antibody D2.3 and its complexes with a substrate analogue and with one of the reaction products are analyzed. Together with the structure of the phosphonate transition state analogue hapten complex, these crystal structures provide a complete description of the reaction pathway. At alkaline pH, D2.3 acts by preferential stabilization of the negatively charged oxyanion intermediate of the reaction that results from hydroxide attack on the substrate. A tyrosine residue plays a crucial role in catalysis: it activates the ester substrate and, together with an asparagine, it stabilizes the oxyanion intermediate. A canal allows facile diffusion of water molecules to the reaction center that is deeply buried in the structure. Residues bordering this canal provide targets for mutagenesis to introduce a general base in the vicinity of the reaction center