Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL

Abstract

Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and safety. In this study, we developed a novel CAR structure based on KIRS2/Dap12 for B cell acute lymphoblastic leukemia (B-ALL) antigen CD19 and compared the anti-tumor efficacy and safety of this construct in transduced T cells with standard second-generation CAR-T cells targeting CD19 for B-ALL in vitro and in vivo and in adult relapsed/refractory (r/r) B-ALL patients. We discovered that KIRS2/Dap12 receptor infused with 4-1BB co-stimulation domain could enhance anti-tumor efficacy by remarkably increasing the production of pro-inflammatory interleukin-2 (IL-2), especially when co-cultured with antigen-positive tumor cells. In addition, CD19-KIRS2/Dap12-BB CAR-T cells showed the inspiring outcome that complete responses were seen in 4 of 4 (100%) patients without neurotoxicity and a high rate of severe cytokine release syndrome (CRS) after CAR-T infusion in a phase I clinical trial. Given these encouraging findings, CD19-KIRS2/Dap12-BB CAR-T cells are safe and can lead to clinical responses in adult patients with r/r B-ALL, indicating that further assessment of this therapy is warranted. Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and safety. In this study, we developed a novel CAR structure based on KIRS2/Dap12 for B cell acute lymphoblastic leukemia (B-ALL) antigen CD19 and compared the anti-tumor efficacy and safety of this construct in transduced T cells with standard second-generation CAR-T cells targeting CD19 for B-ALL in vitro and in vivo and in adult relapsed/refractory (r/r) B-ALL patients. We discovered that KIRS2/Dap12 receptor infused with 4-1BB co-stimulation domain could enhance anti-tumor efficacy by remarkably increasing the production of pro-inflammatory interleukin-2 (IL-2), especially when co-cultured with antigen-positive tumor cells. In addition, CD19-KIRS2/Dap12-BB CAR-T cells showed the inspiring outcome that complete responses were seen in 4 of 4 (100%) patients without neurotoxicity and a high rate of severe cytokine release syndrome (CRS) after CAR-T infusion in a phase I clinical trial. Given these encouraging findings, CD19-KIRS2/Dap12-BB CAR-T cells are safe and can lead to clinical responses in adult patients with r/r B-ALL, indicating that further assessment of this therapy is warranted. IntroductionAdoptive T cell therapy (ACT) involves the manufacture of a patient’s T cells followed by infusion of these engineered T cells into the patient with cancer.1Neelapu S.S. Locke F.L. Bartlett N.L. Lekakis L.J. Miklos D.B. Jacobson C.A. Braunschweig I. Oluwole O.O. Siddiqi T. Lin Y. et al.Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.N. Engl. J. Med. 2017; 377: 2531-2544Google Scholar,2Leon E. Ranganathan R. Savoldo B. Adoptive T cell therapy: Boosting the immune system to fight cancer.Semin. Immunol. 2020; 49: 101437Google Scholar In recent years, chimeric antigen receptor (CAR) T cell immunotherapy, based on the infusion of engineered autologous T cells to recognize the tumor-associated antigens expressed on cancer cells, has changed the modality of treatment for hematological malignancies.3Abramson J.S. Palomba M.L. Gordon L.I. Lunning M.A. Wang M. Arnason J. Mehta A. Purev E. Maloney D.G. Andreadis C. et al.Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.Lancet. 2020; 396: 839-852Google Scholar,4Schuster S.J. Svoboda J. Chong E.A. Nasta S.D. Mato A.R. Anak Ö. Brogdon J.L. Pruteanu-Malinici I. Bhoj V. Landsburg D. et al.Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas.N. Engl. J. Med. 2017; 377: 2545-2554Google Scholar Specifically, CAR-T cells targeting CD19 or B cell maturation antigen (BCMA) in treating B cell lymphoma, leukemia, and multiple myeloma have achieved unprecedented response rates.5Park J.H. Rivière I. Gonen M. Wang X. Sénéchal B. Curran K.J. Sauter C. Wang Y. Santomasso B. Mead E. et al.Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia.N. Engl. J. Med. 2018; 378: 449-459Google Scholar,6Raje N. Berdeja J. Lin Y. Siegel D. Jagannath S. Madduri D. Liedtke M. Rosenblatt J. Maus M.V. Turka A. et al.Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma.N. Engl. J. Med. 2019; 380: 1726-1737Google Scholar Synonymous with the outstanding clinical outcome of CAR-T cell therapy in hematological malignancies have been severe toxicities, including cytokine-release syndrome (CRS), neurotoxicity syndrome, CAR-T cell-related encephalopathy syndrome (CRES), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).7Anagnostou T. Riaz I.B. Hashmi S.K. Murad M.H. Kenderian S.S. Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis.Lancet Haematol. 2020; 7: e816-e826Google Scholar Therefore, management of these toxicities has been a major concern for clinical implementation.A growing amount of evidence indicates that CAR toxicity may be linked to the synthetic nature of the receptor design.8Helsen C.W. Hammill J.A. Lau V.W.C. Mwawasi K.A. Afsahi A. Bezverbnaya K. Newhook L. Hayes D.L. Aarts C. Bojovic B. et al.The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity.Nat. Commun. 2018; 9: 3049Google Scholar To improve the safety of CAR-transduced T cells, we previously designed a natural multi-chain immunoreceptor CAR based on the DNAX-activating protein of 12 kDa (Dap12) signaling domain for the first time, which triggers antigen-specific cytotoxicity, cytokine production, and proliferation that is comparable with CD3z-based CARs ex vivo/in vitro for hematological malignancies.9Chen B. Zhou M. Zhang H. Wang C. Hu X. Wang B. Wang E. TREM1/Dap12-based CAR-T cells show potent antitumor activity.Immunotherapy. 2019; 11: 1043-1055Google Scholar,10Wang E. Wang L.C. Tsai C.Y. Bhoj V. Gershenson Z. Moon E. Newick K. Sun J. Lo A. Baradet T. et al.Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors.Cancer Immunol. Res. 2015; 3: 815-826Google Scholar Dap12 is a transmembrane signaling adaptor protein containing a single immunoreceptor tyrosine-based activation motif (ITAM) that has low homology with ITAMs identified in the CD3z chain. The expression of Dap12 has been found in a variety of immune cells, such as natural killer (NK) cells, macrophages, and some T cells, indicating that Dap12 may have a general role in the immune response.11Parham P. Moffett A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution.Nat. Rev. Immunol. 2013; 13: 133-144Google Scholar,12Angata T. Siglecs that Associate with DAP12.Adv. Exp. Med. Biol. 2020; 1204: 215-230Google Scholar Dap12 was originally found to activate NK cells when was with which the activation and of in the and the to and Cancer Immunol. 2018; and receptors in Rev. Scholar receptors have been including and et to the CARs a to the for T cell and we previously found that T cells a KIRS2/Dap12 CAR showed anti-tumor activity without the domains E. Wang L.C. Tsai C.Y. Bhoj V. Gershenson Z. Moon E. Newick K. Sun J. Lo A. Baradet T. et al.Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors.Cancer Immunol. Res. 2015; 3: 815-826Google Scholar the and CARs or domains or 4-1BB that with the S.J. M. M. The of second-generation chimeric antigen Rev. 2015; The of Cells to 2017; Scholar signaling is for T cell cytotoxicity, and CARs could and the signaling D. M. A. E. X. et by 2017; E. R. R. S. H. J. M. et and 4-1BB Chimeric Antigen T Cancer Res. 2019; Scholar a signaling domain on a CAR may that the of T cell and the of co-stimulation for T cell activation and of we a of receptors the KIRS2/Dap12 with in this To are to a T cell response and T cell activity, we of KIRS2/Dap12 CAR structure and found that T cells antitumor and cytokine we evidence for the efficacy and of the with different in of and hematological a phase I clinical using autologous T cells CAR in adult relapsed/refractory (r/r) B-ALL patients with was to the anti-tumor activity and safety of CD19-KIRS2/Dap12-BB CAR-T cells compared with second-generation CAR-T cells targeting co-stimulation domain KIRS2/Dap12 CAR-T cells comparable activity and robust cytokine domains in CARs can alter of T cells. To the by 4-1BB we the domains of 4-1BB in KIRS2/Dap12 receptor of the domain of with CARs using and a of the different CARs could be expressed to in human T cells the were and the T cells. of T cells could be achieved the of and in To the anti-tumor of the of CAR-T cells, cells that express human CD19 antigen were co-cultured with CAR-T cells in vitro different to for The showed that these engineered T cells comparable activity cells we that T cells 4-1BB KIRS2/Dap12 CAR of interleukin-2 and and when compared with cells KIRS2/Dap12 receptor or the of showed that CAR-T cells express B and CAR-T cells further the human T cell time, we a to and T cell the the of the showed a robust to and CAR-T cells of CAR-T cells the of showed that CAR-T cells expression CAR-T cells infused with Dap12 CAR-T cells the infusion of 4-1BB with different of KIRS2/Dap12 the activity and cytokine production of T cells, we CAR in which 4-1BB is infused with the and the Dap12 The of T cells the on and was with a range to showed that 4-1BB infused with different activity cells 4-1BB infused with the Dap12 T cells robust production T cells CAR in which 4-1BB is infused with the the production of showed the of CAR-T cells and of 4-1BB infusion with different on CAR-T of a KIRS2/Dap12 CAR infused with of the of T cells that express of CAR-T cells was by the and and in the by and CAR-T cells were by Large CAR-T cells show efficacy in hematological malignancies and tumor the anti-tumor of CD19-KIRS2/Dap12-BB CAR-T cells compared with CAR-T cells engineered with a second-generation CAR in in and CD19-KIRS2/Dap12-BB and CD19 CAR-T cells comparable anti-tumor activity in In T cells showed anti-tumor activity and tumor of the CD19 CAR-T cells in that CAR-T cells and CD19 CAR-T cells that T cells of leukemia as as cells, which have been to have potent activity in antitumor activity of and KIRS2/Dap12 CAR-T cells in of the infused with CAR-T on after tumor and were in the of and The the in tumor of the cancer infused with CAR-T on after tumor and were in the of and The showed the in tumor treatment with of or CAR-T Large further the potent anti-tumor activity of T cells a is on the CD19 we CAR targeting In T cells achieved of tumor when compared with T cells. In this we of increasing and CAR-T and found that relapsed by in the the tumor for in the and that the activity of CAR is antigen and CAR-T cells may have high anti-tumor activity the encouraging the in vitro and in vivo we a phase clinical to the and clinical and activity of and and CAR-T cells to adult patients with r/r r/r B-ALL to years, previously CAR-T a and and were into the in the patients to the CAR-T cell infusion to The patients and 4 to and were infused with CAR-T cells. 4 were in the CAR-T 4 patients were in the treatment the of different therapy or treatment that the patient has cells cells human in a of CAR-T cell therapy in adult r/r B-ALL patients to T cells for CD19 CAR-T CAR-T cells for the patients were the of CAR-T and of to and to T cell CD19 CAR-T cells were in as and and The to CD19 CAR-T cell treatment is the cytokine release syndrome (CRS), and the are in In the CAR-T in patients and the patients in the patient and patients The of are and and and were to the the patient’s was The was with the patient’s was patient in and were with to to to and were in the the when compared with that the CAR-T I clinical design and the safety of CAR-T cell of the design and patient the first is 4 to to to CAR-T cell The the patient’s after CAR-T cell and in the were by Large of to CAR-T in a and clinical response of CD19 CAR-T anti-tumor efficacy and clinical response of CAR-T cells are on the and of CAR-T cells in The proliferation and of CD19 CAR-T cells were by cell and In the 4 patients achieved the CAR-T which is patients in the CAR-T followed by a with a and patients in achieved complete response with the patient with system leukemia CAR-T cells achieved as by patients CAR-T cells achieved which is the patients infused with CAR-T cells, to a high rate was of 4 patients infused with CAR-T cells relapsed in and patients after of 4 patients CAR-T cells relapsed in and 4 patients were to the recent that adult r/r B-ALL patients can the CAR-T clinical response of CAR-T CAR-T cell and in was by CAR-T cell and in were by the patients achieved the to and patient in Large cell therapy is as a promising for hematologic with the for a single J.S. Palomba M.L. Gordon L.I. Lunning M.A. Wang M. Arnason J. Mehta A. Purev E. Maloney D.G. Andreadis C. et al.Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.Lancet. 2020; 396: 839-852Google L. CAR T cell for patients with multiple Rev. Scholar We have that a receptor with antigen-specific cytotoxicity, cytokine production, and proliferation that is comparable with second-generation CD3z-based CARs in a of domains in CARs has been to enhance anti-tumor efficacy of CAR-T cells, and activation by domain may T cell In recent years, co-stimulation receptors 4-1BB or were to second-generation the CAR-T cells engineered with a targeting domain and to anti-tumor R. P. N. domains for chimeric antigen and clinical 2019; B. C.A. E. Z. et and of chimeric antigen T cells in S. C. A. T. V. M. et CAR T cell and 4-1BB 2018; 3: Scholar is that of in CARs is to T cell persistence, and anti-tumor clinical CAR-T cells that of the or 4-1BB domain CAR-T cell persistence, cytotoxicity, and a M. M. et T cell by signaling of chimeric antigen Med. 2015; V. A. Lin C. D. L. et of chimeric antigen receptor signaling and that cell 2018; 11: Z. M. J. M. of Engineered and of CAR T 2015; Scholar domains with the KIRS2/Dap12 receptor may enhance anti-tumor efficacy of T with the KIRS2/Dap12 receptor and a of 4-1BB co-stimulation domains in We that 4-1BB KIRS2/Dap12 T cells with comparable anti-tumor efficacy and robust cytokine T cells the anti-tumor efficacy in of B cell and which that targeting CD19 or may be for treating hematologic malignancies or we the safety and anti-tumor efficacy of CAR-T cells in adult r/r B-ALL patients compared with the standard second-generation CAR-T cells. We CAR-T cells and in as the and of CAR-T cells were in the The of CAR-T in is CAR-T achieved patients in the achieved the patients CAR-T cell treatment achieved patients in the CAR-T to which is with their in the after CAR-T cell patient with system leukemia CAR-T treatment achieved that CAR-T cells can into the tumor and antitumor in and the of the promising high a major for CD19 CAR-T cell CAR-T cell treatment can a complete as of 4 patients relapsed on the and of 4 patients CAR-T treatment relapsed with antigen-positive on and infusion and patients of CAR-T cells is of the for antigen-positive and CAR-T cells may the human CAR-T cell persistence, and may in the Wang Chimeric antigen receptor and design 2020; R. X. Y. L. Y. L. Zhang C. Zhang X. in CAR-T cell 2020; 13: S. S. CAR T cells to J. 2020; Scholar which is as a response CAR-T cell activation and is the acute toxicity of CAR-T cell M.L. M. Wang L. C.A. K. C. P. management of chimeric antigen receptor (CAR) T-cell R. C. of Chimeric Antigen Receptor (CAR) T-Cell and for Med. 2020; Scholar In study, 4 patients in the CAR-T the and of with of 4 patients severe patients the and of with of 4 patients severe in the CAR-T is with CAR-T cell therapy and is by the of into with cytokine release syndrome and neurotoxicity after CD19 CAR-T cell 2019; Scholar neurotoxicity in patient system that T cells safety and anti-tumor efficacy for adult r/r B-ALL autologous T cells CD19 could and responses with in with r/r B-ALL and a promising The CAR a toxicity and anti-tumor activity in B cell the of the B-ALL, including high tumor and for antigen-positive or to in CD19 and of CAR-T and CAR-T may further the safety and long-term efficacy of this and of CAR was designed by a the transmembrane and domain of containing which a and Dap12 by the in with the 4-1BB domain and were The CAR was and into the as previously B. Zhou M. Zhang H. Wang C. Hu X. Wang B. Wang E. TREM1/Dap12-based CAR-T cells show potent antitumor activity.Immunotherapy. 2019; 11: 1043-1055Google Scholar,10Wang E. Wang L.C. Tsai C.Y. Bhoj V. Gershenson Z. Moon E. Newick K. Sun J. Lo A. Baradet T. et al.Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors.Cancer Immunol. Res. 2015; 3: 815-826Google and and cells were in a containing and cells were in with The cells were in with cells were by of CD19 cell in this were by and for by using for the of human T cells was using a and cells in were with the and and the containing the CAR using and containing was and by in was by and of CAR-T cell cells were and T cells were and with T cells were in with and autologous the T cells were transduced with CAR and cell were and and the was the of T cells was by using T cells are for in vitro and in vivo of CAR-T cells for and were cell of clinical CD19 CAR-T patients and T cells, were and with a in with autologous and of human T cells were transduced with CD19 CAR in in the of of was by after and CAR-T cells were in to cell in complete with of for the of CAR-T cells were in to the in of CAR-T cells for and were cell of CAR-T cells, and CAR-T cells with cells were using the to the of was into by using for to the the was on the using to the The was as and the were with and to to cells. The of in this are in were as previously to were the of and were with cells or cells in a of The with tumor were infused with CAR-T cells on and and were for of as by of and tumor were by the on the of of the and were in with the for the and of of the of of the on T cells was using followed by with or with cells were for cell to T cell and The were and were on or and cytokine cell proliferation was with a T cells were and with for The was by with and with the CAR-T cells were or a of with cells for were to cytokine of cytokine was using and to the were in and compared multiple with a standard was using the and cells cells were to CAR-T cells were to the to different The cell was and for The rate was to the I design and a phase I designed to the and safety of CD19-KIRS2/Dap12-BB CAR-T cells compared with standard second-generation CAR-T cells. T cells the patients with r/r B cell tumor and were to express a CAR the or with relapsed refractory B-ALL were in this phase I as to the including years, and and of and system leukemia can be patients with cell or patients were to the of the when were and to a complete of patients with including or or and patients with system or system including in the first 12 of the were with or or clinical or with or lymphocytic therapy or severe to the the treatment that the patient is the safety and of the patients with or to in this or and were for or the for that that may the or with the outcome of the may be in clinical patients in this and this was by the review of patients were based on the and of that were for CAR T cell were into to CD19 CAR-T cells or CAR-T cells with using and and 4 and to CD19 CAR-T cells was in this patients were to the CAR-T persistence, and the to Cancer of toxicity and toxicity that with CD19 CAR-T cells, such as and To the of CAR-T cells, were on the and after the the to were on the and the were for patient or patients and after CD19 CAR-T cell infusion using a cytokine the In with the we the human cytokine standard with the to standard We the using the human was by of was or patients after of in vivo and in vitro in this was on and of the were as The different was by using and a to or was as and to was and by and of The was and to of and the of this are the and the on IntroductionAdoptive T cell therapy (ACT) involves the manufacture of a patient’s T cells followed by infusion of these engineered T cells into the patient with cancer.1Neelapu S.S. Locke F.L. Bartlett N.L. Lekakis L.J. Miklos D.B. Jacobson C.A. Braunschweig I. Oluwole O.O. Siddiqi T. Lin Y. et al.Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.N. Engl. J. Med. 2017; 377: 2531-2544Google Scholar,2Leon E. Ranganathan R. Savoldo B. Adoptive T cell therapy: Boosting the immune system to fight cancer.Semin. Immunol. 2020; 49: 101437Google Scholar In recent years, chimeric antigen receptor (CAR) T cell immunotherapy, based on the infusion of engineered autologous T cells to recognize the tumor-associated antigens expressed on cancer cells, has changed the modality of treatment for hematological malignancies.3Abramson J.S. Palomba M.L. Gordon L.I. Lunning M.A. Wang M. Arnason J. Mehta A. Purev E. Maloney D.G. Andreadis C. et al.Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.Lancet. 2020; 396: 839-852Google Scholar,4Schuster S.J. Svoboda J. Chong E.A. Nasta S.D. Mato A.R. Anak Ö. Brogdon J.L. Pruteanu-Malinici I. Bhoj V. Landsburg D. et al.Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas.N. Engl. J. Med. 2017; 377: 2545-2554Google Scholar Specifically, CAR-T cells targeting CD19 or B cell maturation antigen (BCMA) in treating B cell lymphoma, leukemia, and multiple myeloma have achieved unprecedented response rates.5Park J.H. Rivière I. Gonen M. Wang X. Sénéchal B. Curran K.J. Sauter C. Wang Y. Santomasso B. Mead E. et al.Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia.N. Engl. J. Med. 2018; 378: 449-459Google Scholar,6Raje N. Berdeja J. Lin Y. Siegel D. Jagannath S. Madduri D. Liedtke M. Rosenblatt J. Maus M.V. Turka A. et al.Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma.N. Engl. J. Med. 2019; 380: 1726-1737Google Scholar Synonymous with the outstanding clinical outcome of CAR-T cell therapy in hematological malignancies have been severe toxicities, including cytokine-release syndrome (CRS), neurotoxicity syndrome, CAR-T cell-related encephalopathy syndrome (CRES), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).7Anagnostou T. Riaz I.B. Hashmi S.K. Murad M.H. Kenderian S.S. Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis.Lancet Haematol. 2020; 7: e816-e826Google Scholar Therefore, management of these toxicities has been a major concern for clinical implementation.A growing amount of evidence indicates that CAR toxicity may be linked to the synthetic nature of the receptor design.8Helsen C.W. Hammill J.A. Lau V.W.C. Mwawasi K.A. Afsahi A. Bezverbnaya K. Newhook L. Hayes D.L. Aarts C. Bojovic B. et al.The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity.Nat. Commun. 2018; 9: 3049Google Scholar To improve the safety of CAR-transduced T cells, we previously designed a natural multi-chain immunoreceptor CAR based on the DNAX-activating protein of 12 kDa (Dap12) signaling domain for the first time, which triggers antigen-specific cytotoxicity, cytokine production, and proliferation that is comparable with CD3z-based CARs ex vivo/in vitro for hematological malignancies.9Chen B. Zhou M. Zhang H. Wang C. Hu X. Wang B. Wang E. TREM1/Dap12-based CAR-T cells show potent antitumor activity.Immunotherapy. 2019; 11: 1043-1055Google Scholar,10Wang E. Wang L.C. Tsai C.Y. Bhoj V. Gershenson Z. Moon E. Newick K. Sun J. Lo A. Baradet T. et al.Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors.Cancer Immunol. Res. 2015; 3: 815-826Google Scholar Dap12 is a transmembrane signaling adaptor protein containing a single immunoreceptor tyrosine-based activation motif (ITAM) that has low homology with ITAMs identified in the CD3z chain. The expression of Dap12 has been found in a variety of immune cells, such as natural killer (NK) cells, macrophages, and some T cells, indicating that Dap12 may have a general role in the immune response.11Parham P. Moffett A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution.Nat. Rev. Immunol. 2013; 13: 133-144Google Scholar,12Angata T. Siglecs that Associate with DAP12.Adv. Exp. Med. Biol. 2020; 1204: 215-230Google Scholar Dap12 was originally found to activate NK cells when was with which the activation and of in the and the to and Cancer Immunol. 2018; and receptors in Rev. Scholar receptors have been including and et to the CARs a to the for T cell and we previously found that T cells a KIRS2/Dap12 CAR showed anti-tumor activity without the domains E. Wang L.C. Tsai C.Y. Bhoj V. Gershenson Z. Moon E. Newick K. Sun J. Lo A. Baradet T. et al.Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors.Cancer Immunol. Res. 2015; 3: 815-826Google Scholar the and CARs or domains or 4-1BB that with the S.J. M. M. The of second-generation chimeric antigen Rev. 2015; The of Cells to 2017; Scholar signaling is for T cell cytotoxicity, and CARs could and the signaling D. M. A. E. X. et by 2017; E. R. R. S. H. J. M. et and 4-1BB Chimeric Antigen T Cancer Res. 2019; Scholar a signaling domain on a CAR may that the of T cell and the of co-stimulation for T cell activation and of we a of receptors the KIRS2/Dap12 with in this To are to a T cell response and T cell activity, we of KIRS2/Dap12 CAR structure and found that T cells antitumor and cytokine we evidence for the efficacy and of the with different in of and hematological a phase I clinical using autologous T cells CAR in adult relapsed/refractory (r/r) B-ALL patients with was to the anti-tumor activity and safety of CD19-KIRS2/Dap12-BB CAR-T cells compared with second-generation CAR-T cells targeting

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