. 2019 Feb 11;35(2):221-237.e8.

doi: 10.1016/j.ccell.2019.01.002.

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

Hongwei Du¹, Koichi Hirabayashi¹, Sarah Ahn², Nancy Porterfield Kren³, Stephanie Ann Montgomery⁴, Xinhui Wang⁵, Karthik Tiruthani⁶, Bhalchandra Mirlekar³, Daniel Michaud⁷, Kevin Greene⁸, Silvia Gabriela Herrera¹, Yang Xu¹, Chuang Sun¹, Yuhui Chen¹, Xingcong Ma¹, Cristina Rosa Ferrone⁵, Yuliya Pylayeva-Gupta³, Jen Jen Yeh⁹, Rihe Liu¹⁰, Barbara Savoldo¹¹, Soldano Ferrone⁵, Gianpietro Dotti¹²

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁶ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁸ Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
⁹ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Surgery, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁰ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
¹¹ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: gdotti@med.unc.edu.

PMID: 30753824
PMCID: PMC6645919
DOI: 10.1016/j.ccell.2019.01.002

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

Hongwei Du et al. Cancer Cell. 2019.

. 2019 Feb 11;35(2):221-237.e8.

doi: 10.1016/j.ccell.2019.01.002.

Authors

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁶ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁸ Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
⁹ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Surgery, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁰ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
¹¹ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: gdotti@med.unc.edu.

PMID: 30753824
PMCID: PMC6645919
DOI: 10.1016/j.ccell.2019.01.002

Abstract

The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.

Keywords: 4-1BB; B7-H3; CD28; PD-1/PD-L1; chimerc antigen receptor; neuroblastoma; ovarian cancer; pancreatic cancer; solid tumors.

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Figures

**Figure 1.. B7-H3.CAR-Ts Target B7-H3⁺ PDAC Cells**
(A) Representative micrographs of B7-H3 expression in PDAC assessed by staining with the 376.96 mAb at the final concentration of 1 μg/mL. Slides stained only with the secondary Ab were used as a negative control. Scale bars, 200 μm. (B) Expression of B7-H3 in five human PDAC cell lines stained with the 376.96 mAb as assessed by flow cytometry. (Cand D) PDAC cell lines labeled with GFPwere co-cultured with NT, B7-H3.CAR-28ζ-Ts, or B7-H3.CAR-BBζ-TsattheT cell totumor cell ratio of 1 to 5. On day 5, PDAC (GFP⁺) and B7-H3.CAR-Ts (CD3⁺) were enumerated by flow cytometry. Representative flow-cytometry plots (C) and quantification of residual tumor cells (D) are illustrated (n = 4). Error bars denote SD. (E and F) Summary of IFN-γ (E) and IL-2 (F) released by NT, B7-H3.CAR-28ζ-Ts, and B7-H3.CAR-BBζ-Ts in the culture supernatant after 24 h of co-culture with the indicated cell lines as measured by ELISA (n = 4). Error bars denote SD. (G) The Raji cell line was engineered to express h4Ig-B7-H3 via retroviral gene transfer. Cells were sorted based on different expression level of 4Ig-B7-H3, and single clones were expanded. B7-H3 expression of the clones was assessed by staining with the 376.96 mAb and analyzed by flow cytometry. (H and I) Representative flow-cytometry plots of Raji cells (CD4^_CD8^_) and T cells (CD4⁺ or CD8⁺) (H) and summary of residual tumor cells (I) 5 days after Raji wild-type (WT) and Raji 4Ig-B7-H3 clones were co-cultured with NT, CD19.CAR-Ts, B7-H3.CAR-28ζ-Ts, or B7-H3.CAR-BBζ-Tsat 1 to 1 ratio (n = 5). Error bars denote SD; **p < 0.01, one-way ANOVA with Holm-Sidak test adjusted p value. See also Figure S1.

**Figure 2.. B7-H3.CAR-Ts Control PDAC Growth in Xenograft Models**
(A) Schema of the PDAC orthotopic xenograft model infused with CAR-Ts on day 12 after tumor inoculation. (B) Representative bioluminescence images of FFluc-Panc-1 tumor growth in the PDAC orthotopic model shown in (A). (C)Representative ultrasound imaging measurement of the FFluc-Panc-1 tumor on day 50 after tumor implantation in mice treated with CD19.CAR-Ts in the PDAC orthotopic model shown in (A). (C) Representative ultrasound imaging measurement of the FFluc-Panc-1 tumor on day 50 after tumor implantation in mice treated with CD19.CAR-Ts in the PDAC orthotopic model shown in (A).The arrow indicates the tumor. Dimensions of the tumor were 6.85 × 5.85 mm. (D) Bioluminescence kinetics of FFluc-Panc-1 tumor growth (5 mice/group) in the PDAC orthotopic model in (A). (E) Schema of the PDAC orthotopic xenograft model infused with CAR-Ts on day 28 after tumor inoculation. (F and G) Representative bioluminescence images (F) and bioluminescence kinetics (G) of FFluc-Panc-1 tumor growth (5 mice/group) in the PDAC orthotopic model in (E). (H) Schema of the PDAC metastatic model. (I and J) Representative bioluminescence images (I) and bioluminescence kinetics (J) of FFluc-Panc-1 cell growth in the PDAC metastatic model (5 mice/group) in (H). (K) T cells in the blood, spleen, and bone marrowfrom mice in the PDAC metastatic model in (H) euthanized 70 days after CAR-T infusion were identified by the expression of CD45 and CD3 by flow cytometry (5 mice/group). Days indicated in (B), (F), and (I) represent days post T cell infusion. The horizontal bars in (K) represent the mean values. Error bars denote SD; ***p < 0.0001, chi-square test.

Figure 3.. B7-H3.CAR-Ts Target Patient-Derived PDAC *In Vitro* and *In Vivo*
(A) Representative flow plots showing B7-H3 expression in early passages ofthree primary PDAC cell lines established from ascites ofthree PDAC patients and stained with the 376.96 mAb. (B) The primary PDAC cell lineswere labeledwith GFP and co-cultured with NT, B7-H3.CAR-28ζ-Ts, orB7-H3.CAR-BBZ-TsattheTcell to PDAC ratioofl to 5. On day 5, tumor cells (GFP⁺) and T cells (CD3⁺) were enumerated by flow cytometry. (C and D) Summary of residual tumor cells after the co-culture of NT, B7-H3.CAR-28ζ-Ts, and B7-H3.CAR-BBζ-Ts with the primary PDAC cell lines at T cell to tumor cell ratios of 1 to 5 (C) (on day 5, n = 6) and of 1 to 10 (D) (on day 7, n = 4). Error bars denote SD. (E and F) Summary of IFN-γ (E) and IL-2 (F) released in the culture supernatant by NT, B7-H3.CAR-28ζ-Ts, and B7-H3.CAR-BBζ-Ts after 24 h ofco-culture with the primary PDAC cell lines as measured by ELISA (n = 4). Error bars denote SD. (G) CFSE dilution of CFSE-labeled B7-H3.CAR-28ζ-Tsand B7-H3.CAR-BBζ-Tsco-cultured with the primary PDAC cell lines for 5 daysat 1 to 1 ratioanalyzed by flow cytometry. CFSE-labeled T cells alone were used as control. (H) Representative micrographs of B7-H3 expression in PDAC-PDX engrafted into the pancreas of NSG mice assessed by staining with the 376.96 mAb at the final concentration of 1 μg/mL. Slides stained only with the secondary Ab were used as a negative control. Scale bars, 200 μm. (I-K) Representative ultrasound images oftumors (dotted circles marked the tumors) (I) and summary ofthe tumorvolumes measured by ultrasound imaging in the first (J) and the second (K) experiment of the PDAC-PDX xenograft model (5 mice/group in each experiment). Error bars denote SD. Scale bars, 5 mm.

**Figure 4.. 4–1BB Co-stimulation Promotes Low Expression of PD-1 and Better Antitumor Activity against PDAC Tumor Cells Constitutively Expressing PD-L1**
Schema of the Panc-1 tumor rechallenge model In which mice were rechallenged with tumor cells at days 28, 49, and 63 after CAR-Ts Infusion. (B and C) Representative bioluminescence images (B) and bioluminescence kinetics (C) of the FFluc-Panc-1 tumor growth in the model shown in (A) (5 mice/group). (D-I) Circulating CAR-Ts(CD45⁺CD3⁺) (D-F) and PD-1 expression in CAR-Ts(G-I) in mice 22 days(D and G), 48days(Eand H), and 63 days(F and I) after CAR-Ts infusion were examined by flow cytometry (n = 5). *p < 0.05, **p < 0.01, unpaired and non-parametric Mann-Whitney test with two-tailed p value calculation. (J) PD-1 expression in B7-H3.CAR-28ζ-Ts and B7-H3.CAR-BBζ-Ts co-cultured with 2Ig-B7-H3⁺ Raji cells at the T cell to tumor cell ratio of 1 to 1 was analyzed daily from day 1 today 7(n = 8). Error bars denote SD; *p < 0.05, ***p < 0.001, unpaired and non-parametric Mann-Whitney test with two-tailed p value calculation. (K and L) NSG mice were engrafted with the FFluc-BxPC-3 PDAC tumor cell line that constitutively expresses PD-L1 and infused with CAR-Ts on day 14 after tumor inoculation. Representative bioluminescence (K) and bioluminescence kinetics (L) of the FFluc-BxPC-3 PDAC tumor cell line (5 mice/group). (M) Kaplan-Meier survival curve of mice in (K) (5 mice/group), *p = 0.0158 (B7-H3.CAR-28ζ versus B7-H3.CAR-BBζ), **p = 0.0039 (CD19.CAR-28ζ versus B7-H3.CAR-28ζ), chi-square test. In this model for the survival curve, mice were censored when the luciferase signal reached 3.5 × 10⁹ photons per second. Days indicated in (B) and (K) represent the days post T cell infusion. The horizontal bars in (D) to (I) represent the mean values. See also Figure S2.

Figure 5.. B7-H3.CAR-Ts Target B7-H3⁺ OC and NB Cancer Cells Both *In Vitro* and *In Vivo*
(A)Representative micrographs of B7-H3 expression in normal ovary and OC assessed by staining with the 376.96 mAb at the final concentration of 1 μg/mL. Scale bars, 200 μm. (B) Expression of B7-H3 in three human OC cell lines assessed by flow cytometry after staining with the 376.96 mAb. (C) Summary of residual tumor cells in the culture on day 5 of co-culture of NT, B7-H3.CAR-28ζ-Ts, and B7-H3.CAR-BBζ-Ts with OC cell lines at T cell to tumor cell ratio of 1 to 5 (n = 5). Error bars denote SD. (D and E) Summary of IFN-γ (D) and IL-2 (E) released by NT, B7-H3.CAR-28ζ-Ts, and B7-H3.CAR-BBζ-Ts in the co-culture supernatant collected after 24 h and measured by ELISA (n = 5). Error bars denote SD. (F and G) Representative bioluminescence images (F)and bioluminescence kinetics (G) of FFluc-SK-OV-3tumorgrowth upon intraperitoneal (i.p.) inoculation into NSG mice (5 × 10⁵ cells/mouse) and treatment 14days later with i.p. inoculation of CD19.CAR-Ts, B7-H3.CAR-28ζ-Ts, and B7-H3.CAR-BBζ-Ts (5 × 10⁶ cells/ mouse). Error bars denote SD; ***p < 0.0001, chi-square test. (H) Kaplan-Meier survival curve of mice developing OC (5 mice/group). **p = 0.0091, chi-square test. (I) Representative micrographs of B7-H3 expression in NB assessed by staining with the 376.96 mAb at the final concentration of 1 μg/mL. Scale bars, 200 μm. (J) Expression of B7-H3 in human NB tumor cell lines stained with the 376.96 mAb and assessed by flow cytometry. (K) Summary of residual tumor cells in the culture on day 5 of co-culture of NT, B7-H3.CAR-28ζ-Ts, and B7-H3.CAR-BBζ-Ts with NB tumor cell lines at T cell to tumor cell ratio of 1 to 5 (n = 8). Error bars denote SD. (L and M) Summary of IFN-γ (L) and IL-2 (M) released by NT, B7-H3.CAR-28ζ-Ts, and B7-H3.CAR-BBζ-Ts in the co-culture supernatant collected after 24 h and measured by ELISA (n = 8). Error bars denote SD. (N and O) Representative bioluminescence images (N) and kinetics of the bioluminescence (O) of the FFluc-CHLA-255 tumor growth upon intravenous (i.v.) injection into NSG mice (2 × 10⁶ cells/mouse) and i.v. infusion with CD19.CAR-Ts(5 × 10⁶ cells/mouse) or B7-H3.CAR-28ζ-Ts (2 × 10⁶ or 5 × 10⁶cells/mouse) 14 days later (5 mice/group). Error bars denote SD; ***p < 0.0001, chi-square test. (P) Kaplan-Meier survival curve of mice developing metastatic NB (5 mice/group), **p = 0.0035 (CD19.CAR-28ζ versus B7-H3.CAR-28ζ (2 × 10⁶ cells/mouse)), **p = 0.0018 (B7-H3.CAR-28ζ 2 × 10⁶ versus 5 × 10⁶ cells/mouse), chi-square test. Days indicated in (F) and (N) represent the days post T cell infusion. See also Figure S3.

**Figure 6.. Pattern of B7-H3 Expression in Human Normal Tissues**
(A and B) Representative micrographs of B7-H3 expression in PDAC (A) and in indicated normal human organs (B) assessed by staining with the 376.96 mAb at the final concentration of 1 μg/mL. Slides stained only with the secondary Ab were used as a negative control. Black boxes indicate 3-fold zoomed-in cutout. Micrographs are representative of at least three sections per tissue. Scale bars, 200 μm. (C) Summary of the positive score of B7-H3 in human normal tissues. Dotted line indicates the background level of the staining. Error bars denote SD. See also Table S1.

**Figure 7.. B7-H3.CAR-Ts Do Not Cause Loss of Cell Subsets in the Blood, Bone Marrow, Spleen, and Lymph Nodes in Immunocompetent Mice**
(A) Representative flow plots illustrating mB7-H3 expression in the wild-type (WT) murine PDAC cell line KPC-4662 and the same cell line engineered to express mB7-H3 via retroviral gene transfer (mB7-H3-Tg). WT and mB7-H3-Tg KPC-4662 cells were stained with the 376.96 mAb. (B) Representative flow-cytometry plots of WT and mB7-H3-Tg KPC-4662 cells 5 days after co-culture with murine non-transduced T cells (NT), mCD19.CAR-Ts or mB7-H3.CAR-Ts at T cell to tumor cell ratio of 1 to 2. WT and mB7-H3-Tg KPC-4662 cells were identified by SSC-A and mB7-H3 expression, respectively. (C and D) Summary of residual WT KPC-4662 cells (C) and mB7-H3-Tg KPC-4662 cells (D) in the co-culture experiments in (B) (n ≥ 3). ****p < 0.0001, one-way ANOVA with Holm-Sidak test adjusted p value. (E and F) IFN-γ (E) and IL-2 (F) released by NT, mCD19.CAR-Ts, and B7-H3.CAR-Ts after 24 h in the co-culture experiments in (B) as measured by ELISA (n = 3). Error bars denote SD. (G) Murine bone marrow-derived dendritic cells(BMDCs) treated without orwith 100 ng/mLLPSfor2 days were stained with the 376.96 mAb or the EPNCIR122 mAb, and the expression of mB7-H3 was assessed by flow cytometry. (H) IFN-γ released by NT, mCD19.CAR-Ts, and mB7-H3.CAR-Ts after 24 h of co-culture with BMDC streated without or with 100 ng/mL LPS for 2 days at T cell to target cell ratio of 1 to 1 as measured by ELISA (n = 3). Error bars denote SD. (I-K) C57BL/6 micewere irradiated with 400 cGyand 2 days later infused i.v. with syngeneic NT, mCD19.CAR-Ts, ormB7-H3.CAR-Ts (1 × 10⁷ cells/mouse). Mice were euthanized 15–16 days post T cell infusion to analyze the immune cell composition of the blood (I), spleen (J), and bone marrow (K) by flow cytometry (5 mice/group). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, one-way ANOVA with Holm-Sidak test adjusted p value. The horizontal bars in (C), (D), and (I) to (K) represent the mean values. See also Figures S4–S7; Tables S2 and S3.

**Figure 8.. B7-H3.CAR-Ts Control Tumor Growth in Immunocompetent Mice without Causing Evident Toxicity**
(A) Schema of the murine PDAC orthotopic xenograft model. (B) Summary of the tumor volume measured by ultrasound imaging (n = 5 per group). Error bars denote SD; *p = 0.0476 (day 9) and *p = 0.0278 (day 28), unpaired and non-parametric Mann-Whitney test with two-tailed p value calculation. (C) Summary of the tumor weight at the end of the experiment (day 33–34 after T cell infusion) (n = 5 per group). *p = 0.0157, unpaired and non-parametric Mann-Whitney test with two-tailed p value calculation. (D and E) Quantification of mB7-H3.CAR copy numbers by qPCR to evaluate CAR-Ts persistence in the spleens (D) and tumors (E) at the end of the experiment (day 33 – 34 after T cell infusion). (F and G) Cell subset composition of the blood (F) and spleens (G) was analyzed by flow cytometry (n = 5 per group). *p = 0.0159, unpaired and non-parametric Mann-Whitney test with two-tailed p value calculation. (H) Tissue pathology of the indicated organs was evaluated by H&E staining at the end of the experiment (days 33 – 34 after T cell infusion). Scale bars, 200 μm. The horizontal bars in (C) to (G) represent the mean values. See also Figure S8 and Table S4.

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Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

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Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

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