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Is B7-H3 (PD-L2) the Target We Need for Prostate Cancer to Come into the Antibody Drug Conjugate Era?

Although anti-PD-1 or -PD-L1 (B7-H1) therapy is efficacious as an immunotherapy target for multiple malignancies, including bladder and renal cancers, we have not seen significant efficacy in prostate cancer, either as a single agent or in combination therapy regimens.1, 2  There are, of course, exceptions, as a patient with mismatch repair deficiency, microsatellite instability, and/or hypermutation, may have an outstanding response to immune checkpoint blockade.3, 4  However, estimates of the presence of these predisposing tumor alterations as a predictive marker for response to immune checkpoint blockade for patients with metastatic castration-resistant prostate cancer is low, approximately 3-5% of cases.5


Another member of the B7 family of immunomodulatory type I transmembrane glycoproteins is PD-L2, more commonly termed B7-H3.  Similar to PD-L1, B7-H3 also has immune inhibitory effects, generally mediated by cytotoxic T cells and natural killer cells.6-8  B7-H3 has other pro-tumorigenic effects, such as increased tumor survival, chemotherapy resistance, and promotion of metastasis.9-11  As a result, it is not surprising that B7-H3 expression is correlated with a worse prognosis in prostate cancer.12-14

Unlike PD-L1, which is infrequently expressed in prostate cancer, B7-H3 is highly expressed in multiple tumor types, including prostate cancer.  Expression is higher in metastatic prostate cancer compared to localized disease.13, 14  A recent publication from Guo and colleagues, showed that metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer both expressed membranous B7-H3 at high levels, 97%, and 93%, respectively.15  In this intra-patient biopsy study, there was no significant change, in individual patients, from the hormone-sensitive to the castration-resistant disease state in B7-H3 expression.  Interestingly, in most biopsies, there were cells that did not express B7-H3, but these cells were generally within 1-2 cell distance from cells that did express B7-H3.  This provides a theoretical opportunity for agents, with the potential for bystander effect, to be developed.  For example, antibody drug conjugates (ADCs) may deposit their payload in cells that express B7-H3, but their cytotoxic effect may spill over to neighboring B7-H3-negative expressing cells.  Additionally, B7-H3 does not seem to be highly expressed in normal cells, including normal prostate tissue, increasing the attractiveness of this as a therapeutic target for both ADC payload deposition and immune-based approaches e.g. CAR-T cells.13

Although B7-H3 is highly expressed in many different cancer types, its regulation is distinct from PD-L1.  PD-L1 regulation is induced by interferons released by cytotoxic T cells, resulting in negative feedback on cytotoxic T cell activity.  B7-H3 is directly regulated by androgen receptor, and androgen deprivation therapy can decrease expression.16  The recent publication from Guo and colleagues further supports the significant presence of B7-H3 in prostate cancer, showing association with androgen receptor expression, androgen receptor activity signature, and ERG expression.15  Fitting with prostate cancer biology, is the finding that B7-H3 is particularly overexpressed with tumors with DNA repair gene alterations, including BRCA1 and ATM.15

Pre-clinical work has shown DS-7300a, an ADC targeting B7-H3, with DXD, a topoisomerase I inhibiting payload, has antitumor effect against prostate cancer cell lines and patient derived xenografts.15  In early clinical trial work, DS-7300a was used for the treatment of 54 patients with metastatic castration-resistant prostate cancer, and 18 (33%) patients had response.17  Impressively, 46% of the patients had baseline liver metastases, and 40% of those patients responded.  This is consistent with other ADC studies, where patients with difficult to treat and poor prognostic liver metastases have good response rates.

Below are some clinical trials with different ADCs and CAR-T cells targeting B7-H3 in prostate and other cancers, including other genitourinary malignancies, such as bladder and renal cell carcinoma. 

Highlighted Trials targeting B7-H3 for Patients with Prostate and other Genitourinary Cancers

  • BAT8009 ADC for advanced solid tumors (NCT05405621)
  • Vobramitamab duocarmazine (MGC018) ADC in combination with lorigerlimab (MGD019) bispecific PD-1 X CTLA-4 DART molecule in patients with advanced prostate, renal cell and other solid tumors (NCT05293496)
  • ARTEMIS-001: HS-20093 ADC for advanced solid tumors (NCT05276609)
  • DS-7300a ADC for advanced prostate adenocarcinoma, prostate neuroendocrine, bladder cancer, and other solid tumors (NCT04145622)
  • 4SCAR-276 (4th generation lentiviral chimeric antigen receptor) for advanced solid tumors (NCT04432649)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Antonarakis ES, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol 2019; 38:395-405.
  2. Powles T, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med 2022; 28:144-53.
  3. Schweizer MT, Yu EY. “Matching” the “Mismatch” Repair–Deficient Prostate Cancer with Immunotherapy. Clin Cancer Res 2020; 26:981-3.
  4. Graham LS, et al. Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies. PLoS One 2020; 15:e0233260.
  5. Graham LS, Schweizer MT. Mismatch repair deficiency and clinical implications in prostate cancer. Prostate 2022; 82 Suppl 1:S37-S44.
  6. Chapoval AI, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2001; 2:269-74.
  7. Luo L, et al. B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol 2004; 173:5445-50.
  8. Sun X, et al. Mouse B7-H3 induces antitumor immunity. Gene Ther 2003; 10:1728-34.
  9. Liu Z, et al. Immunoregulatory Protein B7-H3 Regulates Cancer Stem Cell Enrichment and Drug Resistance through MVP-mediated MEK Activation. Oncogene 2019; 38:88-102.
  10. Zhang T, et al. Overexpression of B7-H3 augments anti-apoptosis of colorectal cancer cells by Jak2-STAT3. World J Gastroenterol 2015; 21:1804-13.
  11. Liu F, et al. B7‑H3 promotes cell migration and invasion through the Jak2/Stat3/MMP9 signaling pathway in colorectal cancer. Mol Med Rep 2015; 12:5455-60.
  12. Haffner, MC, et al. Comprehensive Evaluation of Programmed Death-Ligand 1 Expression in Primary and Metastatic Prostate Cancer. Am J Pathol 2018; 188:1478-85.
  13. Benzon B, et al. Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis. Prostate Cancer Prostatic Dis 2017; 20:28-35.
  14. Zang X, et al. B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Proc Natl Acad Sci USA 2007; 104:19458-63.
  15. Guo C, et al. B7-H3 as a Therapeutic Target in Advanced Prostate Cancer. Eur Urol 2023; 83:224-38.
  16. Mendes AA, et al. B7-H3 as a Therapeutic Target in Advanced Prostate Cancer. Cancer 2022; 128:2269-80.
  17. Doi T, et al. (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors: Extended follow-up of a phase I/II study. Ann Oncol (2022) 33 (suppl_7) S197-S224.