Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy

doi:10.1016/j.xcrm.2021.100449

. 2021 Nov 16;2(11):100449.

doi: 10.1016/j.xcrm.2021.100449.

Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy

Yan-Ruide Li¹, Yang Zhou¹, Yu Jeong Kim¹, Yanni Zhu¹, Feiyang Ma², Jiaji Yu¹, Yu-Chen Wang¹, Xianhui Chen³, Zhe Li¹, Samuel Zeng¹, Xi Wang¹, Derek Lee¹, Josh Ku¹, Tasha Tsao¹, Christian Hardoy¹, Jie Huang¹, Donghui Cheng⁴, Amélie Montel-Hagen⁵, Christopher S Seet^{4

6

7}, Gay M Crooks^{4

5

7

8}, Sarah M Larson⁹, Joshua P Sasine^{4

7

10}, Xiaoyan Wang⁶, Matteo Pellegrini^{2

4}, Antoni Ribas^{4

7

11

12}, Donald B Kohn^{1

4

10}, Owen Witte^{1

4

7

12

13}, Pin Wang³, Lili Yang^{1

4

7

13}

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Internal Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

PMID: 34841295
PMCID: PMC8607011
DOI: 10.1016/j.xcrm.2021.100449

Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy

Yan-Ruide Li et al. Cell Rep Med. 2021.

. 2021 Nov 16;2(11):100449.

doi: 10.1016/j.xcrm.2021.100449.

Authors

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Internal Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

PMID: 34841295
PMCID: PMC8607011
DOI: 10.1016/j.xcrm.2021.100449

Abstract

Cell-based immunotherapy has become the new-generation cancer medicine, and "off-the-shelf" cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (^AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of ^AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development.

Keywords: CAR-engineered conventional αβ T cells; HLA-ablated universal HSC-iNKT cells; allogeneic HSC-engineered iNKT cells; allogeneic off-the-shelf cell therapy; allorejection; cancer immunotherapy; chimeric antigen receptor; graft-versus-host disease; hematopoietic stem cell; invariant natural killer T cells.

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Conflict of interest statement

Y.-R.L., Y.J.K., J.Y., P.W., Y. Zhu, G.M.C., A.M.-H., C.S.S., and L.Y. are inventors on patents relating to this study filed by UCLA. Y.J.K. is currently an employee of Nkarta. J.Y. and X.W. are currently employees of Appia Bio. X.C. is currently an employee of Atara Bio. Z.L. is currently an employee of Allogene. S.M.L. is a stockholder of 1200 Pharma and TORL BioTherapeutics. A.R. is a consultant for Amgen, Bristol-Meyers Squibb, Chugai, Genentech-Roche, Merck-MSD, Novartis, and Sanofi; a scientific advisory board member of and stockholder with Advaxis, Apricity, Arcus, Bioncotech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Merus, Rgenix, and Appia Bio; and a co-founder and scientific advisory board member of Lutris, PACT Pharma, and Tango Therapeutics. J.S. is a consultant for Kite and on the speaker bureau for Kite and BMS. D.B.K. is a stockholder and scientific advisory board member of Allogene Therapeutics, Myogene Bio, ImmunoVec and Pluto Therapeutics. O.N.W. currently has consulting, equity, and/or board relationships with Trethera Corporation, Kronos Biosciences, Sofie Biosciences, Breakthrough Properties, Vida Ventures, Nammi Therapeutics, Two River, Iconovir, Appia BioSciences, Neogene Therapeutics, and Allogene Therapeutics. P.W. is a co-founder, stockholder, consultant, and advisory board member of HRain Biotechnology, TCRCure Biopharma, and Appia Bio. G.M.C., C.S.S., and A.M.-H. are cofounders and stockholders of Pluto Immunotherapeutics. L.Y. is a scientific advisor to AlzChem and Amberstone Biosciensec, and a co-founder, stockholder, and advisory board member of Appia Bio. None of the declared companies contributed to or directed any of the research reported in this article. The remaining authors declare no competing interests.

Figures

**Figure 1**
*In vitro* generation of allogenic HSC-engineered iNKT (^AlloHSC-iNKT) cells (A) Experimental design to generate ^AlloHSC-iNKT cells *in vitro*. HSC, hematopoietic stem cell; CB, cord blood; PBSC, peripheral blood stem cell; αGC, α-galactosylceramide; Lenti/iNKT-sr39TK, lentiviral vector encoding an iNKT TCR gene and an sr39TK suicide/positron emission tomography (PET) imaging gene. (B–E) Fluorescence-activated cell sorting (FACS) monitoring of ^AlloHSC-iNKT cell generation. (B) Intracellular expression of iNKT TCR (identified as Vβ11⁺) in CD34⁺ HSCs at 72 h after lentivector transduction. (C) Generation of iNKT cells (identified as iNKT TCR⁺TCRαβ⁺ cells) during stage 1 ATO differentiation culture. A 6B11 monoclonal antibody was used to stain iNKT TCR. (D) Expansion of iNKT cells during stage 2 αGC expansion culture. (E) Expression of CD4/CD8 co-receptors on ^AlloHSC-iNKT cells during stage 1 and stage 2 cultures. DN, CD4/CD8 double negative; CD4 SP, CD4 single positive; DP, CD4/CD8 double positive; CD8 SP, CD8 single positive. (F) Single-cell TCR sequencing analysis of ^AlloHSC-iNKT cells. Healthy donor peripheral blood mononuclear cell (PBMC)-derived conventional αβ T (PBMC-Tc) and iNKT (PBMC-iNKT) cells were included as controls. The relative abundance of each unique T cell receptor (TCR) sequence among the total unique sequences identified for individual cells is represented by a pie slice. (G) Table summarizing experiments that have successfully generated ^AlloHSC-iNKT cells. (H) Yields of ^AlloHSC-iNKT cells generated from multiple HSC donors. Representative of 1 (F) and >10 experiments (A–E).

**Figure 2**
Characterization and gene profiling of ^AlloHSC-iNKT cells (A) FACS detection of surface markers on ^AlloHSC-iNKT cells. PBMC-iNKT and PBMC-Tc cells were included as controls. (B and C) Antigen responses of ^AlloHSC-iNKT cells. ^AlloHSC-iNKT cells were cultured for 7 days, in the presence or absence of αGC (denoted as αGC or Vehicle, respectively). (B) Cell growth curve (n = 3). (C) ELISA analyses of cytokine (IFN-γ, TNF-α, IL-2, IL-4 and IL-17) production at day 7 post αGC stimulation (n = 3). (D) FACS detection of intracellular cytokines and cytotoxic molecules in ^AlloHSC-iNKT cells. PBMC-iNKT and PBMC-Tc cells were included as controls. (E–I) Deep RNA-seq analysis of ^AlloHSC-iNKT cells generated from CB- or PBSC-derived CD34⁺ HSCs (n = 3 for each). Healthy donor PBMC-derived conventional CD4⁻ αβ T (PBMC-αβTc; n = 8), CD4⁻ iNKT (PBMC-iNKT; n = 3), γδ T (PBMC- γδT; n = 6), and NK (PBMC-NK; n = 2) cells were included as controls. N indicates different donors. (E) Principal-component analysis (PCA) plot showing the ordination of all six cell types. (F–I) Heatmaps showing the expression of selected genes encoding transcription factors (F), NK activating and inhibitory receptors (G), tissue inflammatory homing markers (H), and HLA molecules (I) for all six cell types. Representative of 1 (E–I) and 3 (A–D) experiments. Data are presented as the mean ± SEM ns, not significant, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001, by Student’s t test.

**Figure 3**
Tumor targeting of ^AlloHSC-iNKT cells through intrinsic NK function (A and B) FACS analyses of surface NK receptor expression and intracellular cytotoxic molecule production by ^AlloHSC-iNKT cells. PBMC-NK cells were included as a control. (A) Representative FACS plots. (B) Quantification of (A) (n = 9). (C–E) *In vitro* direct killing of human tumor cells by ^AlloHSC-iNKT cells. PBMC-NK cells were included as a control. Both fresh and frozen-thawed cells were studied. Five human tumor cell lines were studied: A375 (melanoma), K562 (myelogenous leukemia), H292 (lung cancer), PC3 (prostate cancer), and MM.1S (multiple myeloma). All tumor cell lines were engineered to express firefly luciferase and green fluorescence protein (FG) dual reporters. (C) Experimental design. (D and E) Tumor killing data of A375-FG human melanoma cells (D) and K562-FG human myelogenous leukemia cells (E) at 24 h (n = 4). (F–H) Tumor killing mechanisms of ^AlloHSC-iNKT cells. NKG2D- and DNAM-1-mediated pathways were studied. (F) Experimental design. (G) Tumor killing data of A375-FG human melanoma cells at 24 h (tumor/iNKT ratio 1:2; n = 4). (H) Tumor killing data of K562-FG human myelogenous leukemia cells at 24 h (tumor/iNKT ratio 1:1; n = 4). (I–K) Studying the *in vivo* antitumor efficacy of ^AlloHSC-iNKT cells in an A375-FG human melanoma xenograft NSG mouse model. (I) Experimental design. BLI, live animal bioluminescence imaging. (J) BLI images showing tumor loads in experimental mice over time. (K) Tumor size measurements over time (n = 4–5). Representative of three experiments. Data are presented as the mean ± SEM. ns, not significant; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001 by Student’s t test (B) or one-way ANOVA (D, E, G, H, and K). See also Figure S1.

**Figure 4**
Tumor targeting of ^AlloHSC-iNKT cells through engineered chimeric antigen receptors (CARs) (A) Experimental design to generate BCMA CAR-engineered ^AlloHSC-iNKT (^AlloBCAR-iNKT) cells *in vitro*. BCMA, B cell maturation antigen; BCAR, BCMA CAR; Retro/BCAR-tEGFR, retroviral vector encoding a BCMA CAR gene as well as a truncated epidermal growth factor receptor (tEGFR) reporter gene. tEGFR was used as a staining marker indicating BCAR expression. (B) FACS analysis of BCAR expression (identified as tEGFR⁺) on ^AlloBCAR-iNKT at 72 h after retrovector transduction. Healthy donor PBMC-T cells transduced with the same Retro/BCAR-tEGFR vector (denoted as BCAR-T cells) were included as a staining control. (C–F) *In vitro* killing of human multiple myeloma cells by ^AlloBCAR-iNKT cells. MM.1S-CD1d-FG, human MM.1S cell line engineered to overexpress human CD1d as well as FG dual reporters. PBMC-T, BCAR-T, and ^AlloHSC-iNKT cells were included as effector cell controls. (C) Experimental design. (D) Diagram showing the tumor-targeting triple mechanisms of ^AlloBCAR-iNKT cells, mediated by NK activating receptors, iNKT TCR, and BCAR. (E) Tumor cell killing by the indicated effector cells with/out the addition of αGC (n = 4). (F) Tumor cell killing by ^AlloBCAR-iNKT cells with/out the blockade of DNAM-1 (n = 4). Tumor cell killing was analyzed at 8-h after co-culture (effector/tumor ratio 5:1). (G–N) Studying the *in vivo* antitumor efficacy of ^AlloBCAR-iNKT cells in an MM.1S-CD1d-FG human multiple myeloma xenograft NSG mouse model. Tumor-bearing mice injected with BCAR-T cells or no cells (vehicle) were included as controls. (G–J) Low-tumor-load condition. (G) Experimental design. (H) BLI images showing tumor loads in experimental mice over time. (I) Quantification of (H) (n = 5). (J) Kaplan-Meier survival curves of experimental mice over a period of 4 months after tumor challenge (n = 5). (K–N) High-tumor-load condition. (K) Experimental design. (L) BLI images showing tumor loads in experimental mice at day 38. (M) Quantification of tumor load in experimental mice over time (n = 5). (N) Kaplan-Meier survival curves of experimental mice over a period of 4 months after tumor challenge (n = 5). Representative of two experiments (K–N) and three experiments (A–J). Data are presented as the mean ± SEM. ns, not significant; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001 by one-way ANOVA (E, F, I, and M), or log rank (Mantel-Cox) test adjusted for multiple comparisons (J and N). See also Figure S2.

**Figure 5**
Safety study of ^AlloHSC-iNKT cells (A and B) Studying the graft-versus-host (GvH) response of ^AlloHSC-iNKT cells using an *in vitro* mixed lymphocyte reaction (MLR) assay. PBMC-Tc cells were included as a responder cell control. (A) Experimental design. PBMCs from four different healthy donors were used as stimulator cells. (B) ELISA analyses of IFN-γ production at day 4 (n = 4). N, no stimulator cells. (C–F) Studying the GvH response of ^AlloHSC-iNKT cells using an NSG mouse xenograft model. Donor-matched PBMC-Tc cells were included as a control. (C) Experimental design. (D) Kaplan-Meier survival curves of experimental mice over time (n = 5). (E) H&E-stained tissue sections. Blank indicates tissue sections collected from control NSG mice receiving no adoptive cell transfer. Arrows point to mononuclear cell infiltrates. Scale bar, 200 μm. (F) Quantification of (E) (n = 4). (G–I) *In vivo* controlled depletion of ^AlloHSC-iNKT cells via GCV treatment. GCV, ganciclovir. (G) Experimental design. (H) FACS detection of ^AlloHSC-iNKT cells in the liver, spleen, and lung of NSG mice at day 5. (I) Quantification of (G) (n = 4). Representative of two experiments. Data are presented as the mean ± SEM. ns, not significant; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001 by one-way ANOVA (B), Student’s t test (F and I), or log rank (Mantel-Cox) test adjusted for multiple comparisons (D). See also Figure S3.

**Figure 6**
Immunogenicity study of ^AlloHSC-iNKT cells (A–C) Studying allogenic T cell response against ^AlloHSC-iNKT cells using an *in vitro* MLR assay. Irradiated ^AlloHSC-iNKT cells (as stimulators) were co-cultured with donor-mismatched PBMC cells (as responders). Irradiated PBMC-iNKT and PBMC-Tc cells were included as stimulator cell controls. (A) Experimental design. PBMCs from three different healthy donors were used as responders. (B) FACS analyses of HLA-I and HLA-II expression on the indicated stimulator cells (n = 6). (C) ELISA analyses of IFN-γ production at day 4 (n = 3). (D–F) Studying HLA-I/II expression on ^AlloHSC-iNKT cells *in vivo* in an A375-FG human melanoma xenograft NSG mouse model. PBMC-iNKT and PBMC-Tc cells were included as effector cell controls. (D) Experimental design. (E) FACS analyses of HLA-I/II expression on the indicated effector cells isolated from A375-FG solid tumors. (F) Quantification of (E) (n = 5). (G–J) Studying allogenic NK cell response against ^AlloHSC-iNKT cells using an *in vitro* MLR assay. ^AlloHSC-iNKT cells were co-cultured with donor-mismatched PBMC-NK cells. PBMC-iNKT and PBMC-Tc cells were included as controls. (G) Experimental design. (H) FACS analyses of the indicated cells at days 0 and 1. (I) Quantification of (H) (n = 3). (J) FACS analyses of ULBP expression on the indicated cells (n = 5–6). Representative of two (D–F) and three (A–C and G–J) experiments. Data are presented as mean ± SEM. ns, not significant; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001 by Student’s t test (I) or one-way ANOVA (B, C, F, and G). See also Figures S4–S6.

**Figure 7**
Development of HLA-ablated universal HSC-iNKT (^UHSC-iNKT) cells and derivatives (A) Experimental design to generate ^UHSC-iNKT and BCMA CAR-engineered ^UHSC-iNKT (^UBCAR-iNKT) cells. CRISPR, clusters of regularly interspaced short palindromic repeats; Cas 9, CRISPR-associated protein 9; gRNA, guide RNA; B2M, beta-2-microglobulin; CIITA, class II major histocompatibility complex transactivator. (B–D) FACS monitoring of ^UHSC-iNKT and ^UBCAR-iNKT cell generation. (B) Intracellular expression of iNKT TCR (identified as Vβ11⁺) and surface ablation of HLA-I/II (identified as HLA-I/B2M⁻HLA-II⁻) in CD34⁺ HSCs cells at day 5 (72 h after lentivector transduction and 48 h after CRISPR-Cas9 gene editing). (C) Generation of iNKT cells (identified as iNKT TCR⁺TCRαβ⁺ cells) during stage 1 ATO differentiation culture, stage 2 αGC expansion, and stage 3 CAR transduction. Healthy donor PBMC-T cells transduced with the same Retro/BCAR-tEGFR vector was included as a staining control (denoted as BCAR-T cells). (D) Purification of HLA-I/II-negative ^UHSC-iNKT cells using MACS. (E and F) Studying allogenic T cell response against ^UBCAR-iNKT cells using an *in vitro* MLR assay. Irradiated ^UBCAR-iNKT cells (as stimulators) were co-cultured with donor-mismatched PBMCs (as responders). Irradiated ^AlloBCAR-iNKT and conventional BCAR-T cells were included as stimulator cell controls. (E) Experimental design. PBMCs from three different healthy donors were used as responders. (F) ELISA analyses of IFN-γ production at day 4 (n = 3). (G and H) Studying allogenic NK cell response against ^UHSC-iNKT cells using an *in vitro* MLR assay. ^UHSC-iNKT cells were co-cultured with donor-mismatched PBMC-NK cells. ^AlloHSC-iNKT cells were included as a control. (G) Experimental design. (H) FACS quantification of the indicated cells (n = 3). (I–L) Studying the *in vivo* antitumor efficacy of ^UBCAR-iNKT cells in an MM.1S-CD1d-FG human multiple myeloma xenograft NSG mouse model. (I) Experimental design. (J) BLI images showing tumor loads in experimental mice over time. (K) Quantification of (J) (n = 5). (L) Kaplan-Meier survival curves of experimental mice over a period of 4 months after tumor challenge (n = 8). Mice were combined from two independent experiments. Representative of two (I–L) and three (B–H) experiments. Data are presented as mean ± SEM. ns, not significant; ∗∗∗∗p < 0.0001 by Student’s t test (H), one-way ANOVA (F and K), or log rank (Mantel-Cox) test adjusted for multiple comparisons (L). See also Figure S7.

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References

1. Restifo N.P., Dudley M.E., Rosenberg S.A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 2012;12:269–281. - PMC - PubMed
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[1] Restifo N.P., Dudley M.E., Rosenberg S.A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 2012;12:269–281. - PMC - PubMed

[2] Restifo N.P., Dudley M.E., Rosenberg S.A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 2012;12:269–281. - PMC - PubMed

[3] Kalos M., June C.H. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity. 2013;39:49–60. - PMC - PubMed

[4] Kalos M., June C.H. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity. 2013;39:49–60. - PMC - PubMed

[5] Maus M.V., Fraietta J.A., Levine B.L., Kalos M., Zhao Y., June C.H. Adoptive immunotherapy for cancer or viruses. Annu. Rev. Immunol. 2014;32:189–225. - PMC - PubMed

[6] Maus M.V., Fraietta J.A., Levine B.L., Kalos M., Zhao Y., June C.H. Adoptive immunotherapy for cancer or viruses. Annu. Rev. Immunol. 2014;32:189–225. - PMC - PubMed

[7] Labanieh L., Majzner R.G., Mackall C.L. Programming CAR-T cells to kill cancer. Nat. Biomed. Eng. 2018;2:377–391. - PubMed

[8] Labanieh L., Majzner R.G., Mackall C.L. Programming CAR-T cells to kill cancer. Nat. Biomed. Eng. 2018;2:377–391. - PubMed

[9] Mikkilineni L., Kochenderfer J.N. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130:2594–2602. - PMC - PubMed

[10] Mikkilineni L., Kochenderfer J.N. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130:2594–2602. - PMC - PubMed

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Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy

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Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy

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