Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer

Abstract

Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore, EphA10 could be a potential therapeutic target, likely with minimal adverse effects. However, no effective clinical drugs against EphA10 are currently available. Here, we report high expression levels of EphA10 in tumor regions of breast, lung, and ovarian cancers as well as in immunosuppressive myeloid cells in the tumor microenvironment. Furthermore, we developed anti-EphA10 monoclonal antibodies (mAbs) that specifically recognize cell surface EphA10, but not other EphA family isoforms, and target tumor regions precisely in vivo with no apparent accumulation in other organs. In syngeneic TNBC mouse models, we found that anti-EphA10 mAb clone #4 enhanced tumor regression, therapeutic response rate, and T cell–mediated antitumor immunity. Notably, the chimeric antigen receptor T cells derived from clone #4 significantly inhibited TNBC cell viability in vitro and tumor growth in vivo. Together, our findings suggest that targeting EphA10 via EphA10 mAbs and EphA10-specific chimeric antigen receptor–T cell therapy may represent a promising strategy for patients with EphA10-positive tumors. Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore, EphA10 could be a potential therapeutic target, likely with minimal adverse effects. However, no effective clinical drugs against EphA10 are currently available. Here, we report high expression levels of EphA10 in tumor regions of breast, lung, and ovarian cancers as well as in immunosuppressive myeloid cells in the tumor microenvironment. Furthermore, we developed anti-EphA10 monoclonal antibodies (mAbs) that specifically recognize cell surface EphA10, but not other EphA family isoforms, and target tumor regions precisely in vivo with no apparent accumulation in other organs. In syngeneic TNBC mouse models, we found that anti-EphA10 mAb clone #4 enhanced tumor regression, therapeutic response rate, and T cell–mediated antitumor immunity. Notably, the chimeric antigen receptor T cells derived from clone #4 significantly inhibited TNBC cell viability in vitro and tumor growth in vivo. Together, our findings suggest that targeting EphA10 via EphA10 mAbs and EphA10-specific chimeric antigen receptor–T cell therapy may represent a promising strategy for patients with EphA10-positive tumors. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression. Prognosis in patients with advanced TNBC remains poor, in part due to the limited number of effective therapeutic options. In addition, the high risk of recurrence and resistance to chemotherapy in TNBC remains a substantial clinical challenge. Thus, a novel therapeutic strategy for patients with TNBC is considered an unmet medical need (1Harbeck N. Penault-Llorca F. Cortes J. Gnant M. Houssami N. Poortmans P. Ruddy K. Tsang J. Cardoso F. Breast cancer.Nat. Rev. Dis. primers. 2019; 5: 66Crossref PubMed Scopus (729) Google Scholar, 2Carey L.A. Finding the positive in triple-negative breast cancer.Nat. Cancer. 2021; 2: 476-478Crossref PubMed Scopus (1) Google Scholar). Preclinical and clinical data suggest that antitumor immunity is a critical determinant of outcome in TNBC. Specifically, higher quantities of tumor-infiltrating cytotoxic T lymphocytes (CTLs) have been associated with response to chemotherapy and improved survival in TNBC, suggesting that modulating the tumor microenvironment (TME) is a promising therapeutic strategy in TNBC (3Savas P. Salgado R. Denkert C. Sotiriou C. Darcy P.K. Smyth M.J. Loi S. Clinical relevance of host immunity in breast cancer: From TILs to the clinic.Nat. Rev. Clin. Oncol. 2016; 13: 228-241Crossref PubMed Scopus (451) Google Scholar, 4Gruosso T. Gigoux M. Manem V.S.K. Bertos N. Zuo D. Perlitch I. Saleh S.M.I. Zhao H. Souleimanova M. Johnson R.M. Monette A. Ramos V.M. Hallett M.T. Stagg J. Lapointe R. et al.Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers.J. Clin. Invest. 2019; 129: 1785-1800Crossref PubMed Scopus (138) Google Scholar). Indeed, antiprogrammed cell death 1/ligand 1 (anti-PD-1/-L1) immune checkpoint therapy improves survival when used in combination with chemotherapy in patients with PD-L1–positive TNBC (5Emens L.A. Immunotherapy in triple-negative breast cancer.Cancer J. 2021; 27: 59-66Crossref PubMed Scopus (8) Google Scholar). However, most patients with advanced TNBC do not benefit from anti-PD-L1 therapy, possibly because of the heterogeneity and heavy N-linked glycosylation of PD-L1 (6Li M. Li A. Zhou S. Xu Y. Xiao Y. Bi R. Yang W. Heterogeneity of PD-L1 expression in primary tumors and paired lymph node metastases of triple negative breast cancer.BMC Cancer. 2018; 18: 4Crossref PubMed Scopus (62) Google Scholar, 7Wang Y.N. Lee H.H. Hsu D. of PD-L1 N-linked glycosylation cancer therapy and clinical 27: PubMed Scopus Google Scholar, H.H. Y.N. W. Y. M. et of N-linked glycosylation PD-L1 and therapeutic 2019; PubMed Scopus Google Scholar). Notably, PD-L1 levels in to of cancer patients are as as from by H.H. Y.N. W. Y. M. et of N-linked glycosylation PD-L1 and therapeutic 2019; PubMed Scopus Google Scholar, J. Xu J. Yang D. Zhou W. H. C. of and PD-L1 levels in cancer: from Cancer. 2021; PubMed Scopus Google Scholar). Thus, novel therapeutic antitumor immunity are the of receptor tyrosine are to by with ephrin cells K. R. and of and ephrin Rev. PubMed Scopus Google Scholar, receptor and PubMed Scopus Google and progression of including cancer and ephrin to PubMed Scopus Google Scholar, F. A. of and in the PubMed Scopus Google Scholar). in several human and as tumor and and in cancer: and Rev. Cancer. PubMed Scopus Google Scholar, M. family in cancer the of Rev. PubMed Scopus Google Scholar). receptor A10 (EphA10), a of the is not in normal human except in the S. of a novel receptor tyrosine EphA10, in PubMed Scopus Google Scholar, K. Y. S. T. T. M. K. Y. Y. Y. H. Y. S. receptor A10 is a promising target for breast cancers including triple negative breast cancers.J. PubMed Scopus Google Scholar). In EphA10 expression is in cells of tumors and has been associated with poor prognosis in patients with breast, and cancers K. Y. S. T. T. M. K. Y. Y. Y. H. Y. S. receptor A10 is a promising target for breast cancers including triple negative breast cancers.J. PubMed Scopus Google Scholar, Y. F. Yang D. Yang J. D. expression of breast cancer progression by the and PubMed Scopus Google Scholar, Lee Lee H. Lee receptor tyrosine kinase EphA10 in cancer PubMed Scopus Google Scholar, K. T. M. K. Y. Y. Y. H. Y. S. receptor A10 has a potential as a target for a cancer PubMed Scopus Google Scholar, Li D. Yang EphA10 and are in and J. Clin. 2018; Google Scholar). In human breast cancer expression of EphA10, as by has been significantly with lymph node and higher tumor K. S. T. Y. M. K. Y. Y. Y. H. Y. S. Expression of receptor A10 is with lymph node and progression in breast cancer 2: PubMed Scopus Google Scholar). EphA10 and poor as well as limited expression in normal cells that is a of the an target in cancer higher EphA10 expression has been associated with PD-L1 expression and W. Lee H.H. Y.N. Hsu antitumor immunity by PD-L1 2018; PubMed Scopus Google Scholar). of EphA10 in antitumor immunity are limited and to In we monoclonal antibodies (mAbs) with high for EphA10 in vivo. In syngeneic mouse of TNBC, targeting EphA10 with therapeutic mAbs inhibited tumor progression and enhanced antitumor immunity In addition, EphA10-specific chimeric antigen receptor therapy shown to tumor data in of antitumor immunity in TNBC by targeting EphA10 with developed therapeutic mAbs and EphA10 has been to be an target for TNBC a mAb against EphA10 tumor growth in a mouse K. Y. S. T. T. M. K. Y. Y. Y. H. Y. S. receptor A10 is a promising target for breast cancers including triple negative breast cancers.J. PubMed Scopus Google Scholar). Notably, from a syngeneic TNBC mouse that EphA10 via a tumor growth and antitumor immunity W. Lee H.H. Y.N. Hsu antitumor immunity by PD-L1 2018; PubMed Scopus Google suggesting that targeting EphA10 is in cancer no therapeutic antibodies used in the specifically recognize EphA10, which to anti-EphA10 mAbs that the of EphA10 to antitumor immunity in the of a immune In to in TNBC, EphA10 has been shown to in other of as Lee Lee H. Lee receptor tyrosine kinase EphA10 in cancer PubMed Scopus Google and K. T. M. K. Y. Y. Y. H. Y. S. receptor A10 has a potential as a target for a cancer PubMed Scopus Google Indeed, from that the EphA10 significantly higher in tumor tissues in normal in breast including TNBC and levels of EphA10 in breast, lung, and ovarian cancers with of human by and found that levels of EphA10 expression in the tumor regions of cancer significantly higher levels in the normal tissues to the tumors that EphA10 expression is in normal tissues except in the male K. Y. S. T. T. M. K. Y. Y. Y. H. Y. S. receptor A10 is a promising target for breast cancers including triple negative breast cancers.J. PubMed Scopus Google that therapy be for patients with breast cancer and have adverse W. Lee H.H. Y.N. Hsu antitumor immunity by PD-L1 2018; PubMed Scopus Google Scholar). of that in ovarian cancer to in breast and EphA10 expression significantly higher in tumor regions in normal tissues with EphA10 expression to be by the levels of EphA10 expression in in vitro and but EphA10 levels in tumors with have that and cancer cells Y. the tumor microenvironment and ovarian cancer therapeutic 2018; Scopus Google Scholar, J. S. and of PubMed Scopus Google Scholar). EphA10 expression by with as and EphA10 expression could be inhibited in normal except and of EphA10 may be by is to the of EphA10 expression by of EphA10 expression a for EphA10 therapy in with EphA10 tumor we EphA10 is immune cells the which to in cancer immune we with antibodies that recognize target for EphA10 tumor-infiltrating T cells in and immunosuppressive myeloid cells K. Smyth M.J. and immune in the tumor PubMed Scopus Google including in in and in and cells in in and in EphA10 with and as by in but not with T cells in the and are well to antitumor immunity C. A. P. to target to immune 2019; Scopus Google Scholar, S. C. cells that antitumor immunity and are by 2018; PubMed Scopus Google Scholar). EphA10 in tumor regions as well as in immune cell as and and targeting EphA10 by an EphA10 therapeutic in EphA10-positive malignancies, including breast may to effective cancer the of antitumor immune and mAbs targeting EphA10, we used C. of cells of PubMed Scopus Google Scholar, R.M. Lee Li of therapeutic antibodies for the of 27: PubMed Scopus Google with the of human EphA10 derived from cells the with to an immune a with cells by a which the of with and S. S. M. N. for 2016; PubMed Scopus Google Scholar). the and we the cells from the and with of that the anti-EphA10 we the the that and cells but not by the and of and in vivo we and with high antigen for EphA10 EphA10 is in human and mouse with the S. of a novel receptor tyrosine EphA10, in PubMed Scopus Google we the from the that not the human but mouse EphA10 the mAbs to be in the mouse tumor an strategy for we the of and heavy and to be the and we a to the of to EphA10 as well as to other EphA family to a with EphA10 receptor From to 2019; PubMed Scopus Google and found that specifically to EphA10, not to other the of anti-EphA10 we by a to to EphA10 cells and in with the a higher in #4 and in clone cell by the to recognize the of EphA10 the cell #4 and clone cells mouse EphA10 and that anti-EphA10 antibodies to recognize mouse EphA10 the of not EphA10 clone #4 with and of antigen to the and the targeting regions of anti-EphA10 in we anti-EphA10 with and an in tumors of in tumors for suggesting that anti-EphA10 antibodies a normal to that of other antibodies in a mouse of antibodies and in and of and Scholar). the of EphA10 mAb specifically in regions of tumor to EphA10 levels not other from and male a of and of the anti-EphA10 mAbs and the potential to therapeutic antibodies specifically targeting EphA10 in the therapeutic of the anti-EphA10 antibodies in a syngeneic tumor TNBC cells the of by of the clone as a negative the tumor and as a in a In with anti-EphA10 clone tumor with the with from clone #4 from and the of the the of the not significantly Notably, the that clone #4 the most improved response the therapeutic of and response Oncol. Google for clone #4 for clone we clone #4 by therapeutic of and with with clone #4 in to tumor and a higher response the from the that with a higher of clone #4 a response that a and and the mouse tumor including the with clone #4 to tumor and tumor with and suggesting that anti-EphA10 clone #4 may therapeutic to tumor In addition, of clone #4 in in the as not significantly from that of the syngeneic TNBC we in response to clone #4 which a in tumor and tumor in Together, as by syngeneic TNBC models, that our EphA10 clone #4 be a for of therapeutic antibodies against EphA10, which could benefit patients with TNBC the of anti-EphA10 in antitumor we the of anti-EphA10 mAb in and anti-EphA10 mAb not antitumor in immune tumor in suggesting the antitumor immunity is for anti-EphA10 tumor that tumor from the of antitumor immunity in the host S. M. Y. R. immunity in cancer 2019; PubMed Scopus Google we with anti-EphA10 mAb #4 the of a in antitumor immunity that cells by the target A. Y. S. F. in targeting immunity for effective cancer 2018; PubMed Scopus Google which in may to therapeutic tumor we tumors from with anti-EphA10 clone #4 cells to the of cells strategy by and to cell and cell by of including and of anti-EphA10 clone #4 in not the number of T cells and T cells in the of significantly the immunity as by the of and of in T cells with the and EphA10 we the and viability of cells in syngeneic mouse with anti-EphA10 clone #4 strategy by and to cell and cell by of including and the and viability of to in the anti-EphA10 mAb no due to Thus, the that of anti-EphA10 clone #4 not the and viability of and in tumor we developed an EphA10 mAb that could tumor growth in syngeneic TNBC a of antitumor which a therapeutic for TNBC patients EphA10 is T therapy with derived from a mAb is considered as an and effective cancer S. M. S. K. chimeric antigen receptor T to Cancer. 2019; 18: PubMed Scopus Google Scholar). the of therapy with adverse expression of a target be a with of of cancer and combination Rev. Clin. Oncol. 2016; 13: PubMed Scopus Google Scholar). that EphA10 tumor and in most of normal tissues S. of a novel receptor tyrosine EphA10, in PubMed Scopus Google Scholar, K. Y. S. T. T. M. K. Y. Y. Y. H. Y. S. receptor A10 is a promising target for breast cancers including triple negative breast cancers.J. PubMed Scopus Google we that anti-EphA10 mAbs could be to the of EphA10-specific we the human from anti-EphA10 clone #4 a in Scopus Google and and human T cells for of that cells D. T. S. A. C. K. A. J. J. D. M. A. R. A. et for novel chimeric antigen in Clin. PubMed Scopus Google we that the expression levels of cells not with cells suggesting that with EphA10 the cell surface of we human T cells from with and the of T cells cell T cells with of 1 and to by the with by Indeed, the of EphA10 in of cells 2: with the T the of cells in human T cells cells with cells for to data high of surface and in normal T and cell surface significantly in cells to cells and normal T cells that cells be specifically when cancer cells the in vitro of cells EphA10-positive human breast cancer we the by cells with cells T cells with and the of to a N. D. C. S. Preclinical of T cells in a of PubMed Scopus Google Scholar). found that the number of cell significantly cell of cells 2 2 the of for to target for to the enhanced against target cells cell growth by EphA10-specific we the antitumor of cells in vivo by a mouse of cells Y. M. C. H. Y. Y. J. H. C. Yang Li W. T cells for advanced 2018; Scopus Google Scholar, J. S. W. triple-negative breast cancer with combination therapy of T cells and 2021; PubMed Scopus Google Scholar). cells and that the in the to the cell that the a to tumor the Indeed, tumor growth significantly in the to the suggesting the antitumor of the TNBC mouse a of cell in the of with are no of the of cell in vivo and In addition, we found cells cell death in tumor the of the the no in the suggesting the our findings that cells derived from the of anti-EphA10 clone #4 a antitumor in a antigen EphA10 could be an for an P. J. 18: PubMed Scopus Google Scholar, J. W. T. Lee H.H. et of triple-negative breast cancer cells by targeting 2018; PubMed Scopus Google antitumor of the of cytotoxic drugs with in tumor regions for of EphA10-positive the of EphA10 mAbs for we the of EphA10 which is for the to cancer cells via in the antitumor of cytotoxic drugs H. of and the and clinical of 2016; PubMed Scopus Google Scholar). we anti-EphA10 with a and the antibodies in cells of the with from to in the in as which the anti-EphA10 is a of the of anti-EphA10 clone in the of cells in a and to the from the of clone with by that anti-EphA10 clone from the cell surface to be to the be by of as S. of PubMed Scopus Google we are in EphA10 we the of the clone in cells with of and and found that that but not clone suggesting that anti-EphA10 clone the cells in to the of the EphA10 we used a K. H. T. of and PubMed Scopus Google to the by the anti-EphA10 mAb in by the a the from the and the the by an K. T. J. and to PubMed Scopus Google Scholar). EphA10 shown in by A. M. S. R. C. R. T. of and 2018; PubMed Scopus Google by an as a with of heavy in in the by J. J. J. with 2016; PubMed Scopus Google Scholar). Together, the EphA10 in with the the of EphA10 which the EphA10 and be in of targeting that anti-EphA10 clone could be an to the potential for clinical of therapy in the of the that are specifically cancer cells has been used as a therapeutic strategy for breast of breast cancer patients from that target and (1Harbeck N. Penault-Llorca F. Cortes J. Gnant M. Houssami N. Poortmans P. Ruddy K. Tsang J. Cardoso F. Breast cancer.Nat. Rev. Dis. primers. 2019; 5: 66Crossref PubMed Scopus (729) Google Scholar). However, of patients with breast cancer have TNBC, which is negative for and expression. TNBC patients have limited therapeutic and therapeutic due to chemotherapy resistance is a challenge. therapeutic strategy to TNBC is L.A. Finding the positive in triple-negative breast cancer.Nat. Cancer. 2021; 2: 476-478Crossref PubMed Scopus (1) Google Scholar). mAbs in cancer therapy are to target the for and antitumor in tumor in cancer patients M. antibodies in cancer 2016; PubMed Scopus Google Scholar). EphA10 has been to be a surface and a promising therapeutic target for cancer therapy K. Y. S. T. T. M. K. Y. Y. Y. H. Y. S. receptor A10 is a promising target for breast cancers including triple negative breast cancers.J. PubMed Scopus Google Scholar, K. T. M. K. Y. Y. Y. H. Y. S. receptor A10 has a potential as a target for a cancer PubMed Scopus Google Scholar, Li D. Yang EphA10 and are in and J. Clin. 2018; Google Scholar). However, EphA10 is a receptor From to 2019; PubMed Scopus Google Scholar, F. tyrosine with PubMed Scopus Google and therapy but not kinase may be a to target et K. Y. S. T. T. M. K. Y. Y. Y. H. Y. S. receptor A10 is a promising target for breast cancers including triple negative breast cancers.J. PubMed Scopus Google Scholar). tumor in a TNBC mouse by of an anti-EphA10 the could not immune response to the antitumor which is critical for human clinical developed mAbs with high for EphA10 in tumor regions and data to the therapeutic and of anti-EphA10 antibodies in syngeneic TNBC is of that EphA10 therapy to cancer that In we used the TNBC to therapeutic as shown in and the developed EphA10 targeting therapy may be to other cancer including and breast cancer of and other receptor tyrosine in breast cancer.Cancer Rev. 2016; PubMed Scopus Google Scholar, J. C. M. N. J. M. and breast the Rev. Clin. Oncol. PubMed Scopus Google Scholar). Thus, is to the developed EphA10 target therapy breast cancer patients are to the drugs as and in the anti-EphA10 not significantly tumor growth but the and of in tumor our that EphA10 tumor cells and immunosuppressive including and in the findings that EphA10 immune and the and of in the which be with have that EphA is to T cell immunity. of to EphA and T cells is to T cell and T cell K. of EphA cells PubMed Scopus Google Scholar, of T J. PubMed Scopus Google Scholar, J. to T lymphocytes and tyrosine of PubMed Scopus Google Scholar). EphA10 is considered to be a most have been shown to with EphA10 S. of a novel receptor tyrosine EphA10, in PubMed Scopus Google suggesting that death receptor may as an of T cell immunity with other EphA In the by a critical in the of cancer and the immune K. R. and of and ephrin Rev. PubMed Scopus Google Scholar). that from to ephrin is for the of T cells for and in 2019; PubMed Scopus Google Scholar). Thus, be to EphA10 the to ephrin T cells to cytotoxic immunity. be to a in the of EphA10 in antitumor immunity. In to antitumor other critical of anti-EphA10 antibodies high and to the of antibodies potential for the of therapeutic as and therapy has adverse as as therapeutic expression of the target be a with of of cancer and combination Rev. Clin. Oncol. 2016; 13: PubMed Scopus Google Scholar). EphA10 high expression and not in normal tissues except testis, and in vivo that could be from the by the Therefore, that is currently no to our anti-EphA10 antibodies in TNBC may an to in TNBC. Indeed, our the of cells derived from anti-EphA10 clone #4 TNBC tumor and T cell tumor tissues in which may for clinical of cells in TNBC. the other is of the to cancer therapy, of a mAb with a cytotoxic has been used to of cancer by in the tumor and P. J. 18: PubMed Scopus Google Scholar). an with a to an to the antigen by the for TNBC L.A. Finding the positive in triple-negative breast cancer.Nat. Cancer. 2021; 2: 476-478Crossref PubMed Scopus (1) Google Scholar). However, of the for therapy is the of the Notably, EphA10 the of antigen for for as a is cell in tumor regions but not Furthermore, the anti-EphA10 antibodies that in precisely EphA10 in the tumor and but not in other in vivo. In addition, the of the antibodies to the EphA10 the of drugs cells for effects. Therefore, antitumor immunity by targeting EphA10 a for TNBC, and of therapeutic anti-EphA10 antibodies are to the of as and and breast cancer cell from breast cancer cell and mouse cancer cell in and with and cell negative for and by with of the to the of expression by EphA10 the and cells with we via of 1 of with 1 of and of expression in of from the for and a by with cells for for cells with of for 1 and to for to from a of of cell with of the antigen a of in of and EphA10 from in and with of for 1 in and with of anti-EphA10 in for 1 in by with of in in of to well and and in the for with and the a mouse mAb used to the and in a the in vitro EphA10 antibodies 1 EphA10 tumor cells with of anti-EphA10 and in for the cells by with to a in mouse tumor a and used to mouse tumors cells and with cells for to with antibodies against the and cells and with cells with of a by the with tumors from and with for in for In with primary antibodies against and by and antibodies for 1 used for used for anti-EphA10 mAbs and to the the in vivo cells in a of and and the of to male the tumor mouse with of and associated with of an in vivo accumulation as the of in tumors. of tumor tissues and other from and and EphA10 antibodies with to the a of the cells with antibodies and by an used for to by the and the therapeutic of EphA10 antibodies in tumor models, cells in a of and and the of to the tumor and mouse with anti-EphA10 antibodies 2 for a of by the and represent tumor and tumor EphA10 antigen to with in and the to a in as an and in to a of and used to for with data used to the data to a to an and the tumor used to by the and from the with primary antibodies against EphA10 by with and and with and the of positive cells used to the of human anti-EphA10 the that the and and with and cells in a of cells with EphA10 and and and and for to cell by and and T cell cell from and cell and 1 of cells in of with and of as a of the cells from in with and with cells for cells and with of by a and of cells a to cells and cells well with cells with cells as the T cells and with and by a and by cells from of from the of a and human the be with with in the of by the with the a the the in the and for of the the the to a and to a of with to the and by and and for and the the with T cell and 2 in a of 1 of cells and for in the cells by 2 of cells and for to cells in of and the to to the T our of T cells be of in vitro human T cells with and and the of T cell by a T cells in and with T T cells for T cells in 1 of in a of 1 of as a of 2 the cells with for the cells by cell for in the of by a of cells cells be to with cells for the cells and well for in with an the of In our we to of cells and in of cells the of and the with to the the of the and cell of T cells and and In addition, of human a the of tumor of in of by the the the of In the of the be and by and T cells with and the cell with by a a of by of are shown as with of the by the to of considered for not data are the and and H. are as a by of other no for in the mAb and for in monoclonal the of K. of H. W. J. J. Y. J. H. H. H. N. D. H. in part by the an number of and Breast to N. from the of the by the of in of and R. C. and of by the of and and to Breast and in to and to of and to an from the to

Topics & Concepts