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Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody

View Article: PubMed Central - PubMed

ABSTRACT

T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies. Its in vitro tumor cytotoxicity, when expressed as EC50, correlated with the surface HER2 expression in a large panel of human tumor cell lines, irrespective of lineage or tumor type. HER2-BsAb-mediated cytotoxicity was relatively insensitive to PD-1/PD-L1 immune checkpoint inhibition. In four separate humanized mouse models of human breast cancer and ovarian cancer cell line xenografts, as well as human breast cancer and gastric cancer patient-derived xenografts (PDXs), HER2-BsAb was highly effective in promoting T cell infiltration and suppressing tumor growth when used in the presence of human peripheral blood mononuclear cells (PBMC) or activated T cells (ATC). The in vivo and in vitro antitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic.

No MeSH data available.


Related in: MedlinePlus

HER2-BsAb-mediated in vitro T cell cytotoxicity was relatively insensitive to PD-L1 expression on the tumor targets or PD-1 expression on T cells. (A) FACS analysis of PD-L1 expression in HCC1954 cells (left panel), of induced PD-1 expression in ATCs (middle panel), and HER2-BsAb-mediated cytotoxicity (right panel). (B) FACS analysis of PD-L1 expression in HEK-293 cells (left panel), and HER2-BsAb-mediated cytotoxicity using the ATCs as in (A) (middle panel). Mean + SEM (n = 6).
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f0003: HER2-BsAb-mediated in vitro T cell cytotoxicity was relatively insensitive to PD-L1 expression on the tumor targets or PD-1 expression on T cells. (A) FACS analysis of PD-L1 expression in HCC1954 cells (left panel), of induced PD-1 expression in ATCs (middle panel), and HER2-BsAb-mediated cytotoxicity (right panel). (B) FACS analysis of PD-L1 expression in HEK-293 cells (left panel), and HER2-BsAb-mediated cytotoxicity using the ATCs as in (A) (middle panel). Mean + SEM (n = 6).

Mentions: Activation of tumor-specific CTL in the tumor microenvironment is known to promote expression PD-1/PD-L1 leading to T cell exhaustion or suppression, a phenomenon termed “adaptive immune resistance”.21 The presence of PD-1/PD-L1 pathway has also been reported to limit the antitumor effects of T-cell-engaging BsAb.16 To determine if HER2-BsAb had this same limitations, PD-1(+) ATCs were used against the HER2(+) PD-L1(+) breast carcinoma cell line HCC1954 with or without the PD-1-specific antibody pembrolizumab. As shown in Fig. 3A, PD-1(+) T cells generated similar cytotoxic responses in the presence of HER2-BsAb no matter whether pembrolizumab was present or not. When HER2(+) human embryonic kidney cells (HEK-293) were transfected with the full sequence of PD-L1 and used as targets, cytotoxicity against cells expressing PD-L1 was not significantly different to the one observed in non-transfected HEK-293 cells, although maximal cytotoxicity was slightly less with PD-L1(+) HEK-293 versus PD-L1(−) parental HEK-293 (Fig. 3B).Figure 3.


Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody
HER2-BsAb-mediated in vitro T cell cytotoxicity was relatively insensitive to PD-L1 expression on the tumor targets or PD-1 expression on T cells. (A) FACS analysis of PD-L1 expression in HCC1954 cells (left panel), of induced PD-1 expression in ATCs (middle panel), and HER2-BsAb-mediated cytotoxicity (right panel). (B) FACS analysis of PD-L1 expression in HEK-293 cells (left panel), and HER2-BsAb-mediated cytotoxicity using the ATCs as in (A) (middle panel). Mean + SEM (n = 6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5384386&req=5

f0003: HER2-BsAb-mediated in vitro T cell cytotoxicity was relatively insensitive to PD-L1 expression on the tumor targets or PD-1 expression on T cells. (A) FACS analysis of PD-L1 expression in HCC1954 cells (left panel), of induced PD-1 expression in ATCs (middle panel), and HER2-BsAb-mediated cytotoxicity (right panel). (B) FACS analysis of PD-L1 expression in HEK-293 cells (left panel), and HER2-BsAb-mediated cytotoxicity using the ATCs as in (A) (middle panel). Mean + SEM (n = 6).
Mentions: Activation of tumor-specific CTL in the tumor microenvironment is known to promote expression PD-1/PD-L1 leading to T cell exhaustion or suppression, a phenomenon termed “adaptive immune resistance”.21 The presence of PD-1/PD-L1 pathway has also been reported to limit the antitumor effects of T-cell-engaging BsAb.16 To determine if HER2-BsAb had this same limitations, PD-1(+) ATCs were used against the HER2(+) PD-L1(+) breast carcinoma cell line HCC1954 with or without the PD-1-specific antibody pembrolizumab. As shown in Fig. 3A, PD-1(+) T cells generated similar cytotoxic responses in the presence of HER2-BsAb no matter whether pembrolizumab was present or not. When HER2(+) human embryonic kidney cells (HEK-293) were transfected with the full sequence of PD-L1 and used as targets, cytotoxicity against cells expressing PD-L1 was not significantly different to the one observed in non-transfected HEK-293 cells, although maximal cytotoxicity was slightly less with PD-L1(+) HEK-293 versus PD-L1(−) parental HEK-293 (Fig. 3B).Figure 3.

View Article: PubMed Central - PubMed

ABSTRACT

T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies. Its in vitro tumor cytotoxicity, when expressed as EC50, correlated with the surface HER2 expression in a large panel of human tumor cell lines, irrespective of lineage or tumor type. HER2-BsAb-mediated cytotoxicity was relatively insensitive to PD-1/PD-L1 immune checkpoint inhibition. In four separate humanized mouse models of human breast cancer and ovarian cancer cell line xenografts, as well as human breast cancer and gastric cancer patient-derived xenografts (PDXs), HER2-BsAb was highly effective in promoting T cell infiltration and suppressing tumor growth when used in the presence of human peripheral blood mononuclear cells (PBMC) or activated T cells (ATC). The in vivo and in vitro antitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic.

No MeSH data available.


Related in: MedlinePlus