Article Figures & Data
Figures
- Fig. 1.
The B7 family and cancer therapy. A, enhancement of costimulation. B7-1, B7-2, B7h-transfected tumor cell vaccines. Absence of expression of costimulatory B7 molecules renders tumors invisible to the immune system. Therefore, transduction of tumor cells with B7-1, B7-2, and B7h on tumor cell could render tumor cells capable of effective T cell activation if tumor cells also express the appropriate MHC-peptide complex. B, blockade of coinhibition: Anti-CTLA-4 therapy. APC pick up antigens released from tumor cells and present them to naive T cells in the context of B7-1 and B7-2 costimulation. On T cell activation, CTLA-4 is expressed and it begins to perform its inhibitory function. Therefore, specific blockade of CTLA-4, while leaving signals to TCR and CD28 intact, leads to enhanced antitumor immunity and tumor eradication. C, PD-L1/PD-1. Tumor evasion pathway. There is an inverse correlation between tumor PD-L1 expression and poor prognosis of cancer patients. It is a very attractive possibility for tumor immunotherapy by blocking the PD-L1/PD-1 pathway between PD-L1 on tumors and PD-1 on CD8 T cells as well as PD-L1 on APC or activated T cells and PD-1 on T cells. D, tumor-associated B7-H3 and B7x. Last-ditch mechanism. B7-H3 and B7x are the newest members of the B7 family. Both B7-H3 and B7x inhibit T cell functions and are overexpressed on some tumor cells and tumor blood vessels consequently, blockade of tumor-associated B7-H3 and B7x could offer a new dual beneficial therapy: enhancement of T cell-mediated antitumor immunity (immunotherapy) and destruction of tumor vessels (anti angiogenesis).
Tables
- Table 1.
Expression and function of the B7 family ligands and their receptors of the CD28 family
The B7 family ligands The CD28 family receptors Expression Name Name Expression Function Group I APC B7-1 
CD28 T cells Costimulation APC B7-2 CTLA-4 Activated T cells Coinhibition APC, tissue B7h ICOS Activated T cells Costimulation Group II APC, tissue, tumors PD-L1 PD-1 Activated T, B, and myeloid cells Coinhibition APC PD-L2 PD-1 Activated T, B, and myeloid cells Coinhibition Group III APC, tissue, tumors B7-H3 Unidentified receptor Activated T cells Coinhibition Tissue, tumors B7x Unidentified receptor Activated T cells Coinhibition - Table 2.
Phase I/II clinical trials of CTLA-4 blockade
Antibodies Dose Cancer No. of cases No. of objective responses Reference MDX-010 3 mg/kg, 1.5 mg/kg every 4 weeks Lymphoma 4 2 (63) Colon 3 0 Prostate 4 0 MDX-010 3 mg/kg Prostate 14 2 (≥50% decrease of prostate-specific antigen) (58) MDX-010 3 mg/kg every 3 weeks Renal 21 1 partial response (66) 3 mg/kg, 1 mg/kg every 3 weeks Renal 38 5 partial responses MDX-010 3 mg/kg Melanoma 7 0 (57) Ovarian 2 0 MDX-010 3 mg/kg every 4 weeks Melanoma 37 2 partial responses (69) MDX-010 + dacarbazine Melanoma 35 1 complete response 5 partial responses MDX-010 1-3 mg/kg Renal 61 7 (64) MDX-010 ± gp100 peptide 1-9 mg/kg Melanoma 137 20 MDX-010 + gp100 peptide 3 mg/kg every 3 weeks Melanoma 14 2 complete responses (61) 1 partial response MDX-010 + gp100 peptide 3 mg/kg every 3 weeks Melanoma 29 2 complete responses (60) 2 partial responses 1-3 mg/kg, 1 mg/kg every 3 weeks Melanoma 27 3 partial responses MDX-010 + IL-2 1 mg/kg × 3-6 Melanoma 6 1 partial response (65) 2 mg/kg × 3-7 Melanoma 3 1 complete response 3 mg/kg × 1-9 Melanoma 27 2 complete responses 4 partial responses MDX-010 + peptide 0.3-3 mg/kg every 3 weeks Melanoma 19 7 (62) MDX-010 + GVAX 3 mg/kg Prostate 6 5 (≥50% decrease of prostate-specific antigen) (70) CP-675,206 0.01-15 mg/kg × 1 Melanoma 34 2 complete responses (59) 2 partial responses Renal 4 0 Colon 1 0 CP-675, 206 3-10 mg/kg every 4 weeks Melanoma 14 1 (67) CP-675, 206 10 mg/kg every 4 weeks Melanoma 16 3 (68) 15 mg/kg every 12 weeks Melanoma 10 2 - Table 3.
Expression of PD-L1 and PD-L2 in tumors and clinical significance
Cancer No. of samples PD-L1 (%) PD-L2 (%) Clinical association Reference Renal cell carcinoma 196 66 3-fold increased mortality (78) Tumor-infiltrating lymphocytes 59 3.6-fold increased mortality Non–small cell lung cancer 52 100 100 None (79) Breast cancer 44 50 Associated with grade III, and estrogen/progesterone receptors (80) Tumor infiltrating lymphocytes 34 Associated with tumor size, grade III, Her2/neu positive status Gastric carcinoma 102 42.2 Associated with tumor size, invasion, metastasis, and survival (82) Bladder urothelial carcinoma 65 100 Associated with high recurrence and poor survival (84) Bladder urothelial carcinoma 280 36.1 Associated with high-grade tumor infiltrating mononuclear cells (83) Ovarian cancer 70 68.6 Poor prognostic factor for survival (81) Inversely associated with intraepithelial CD8 cells 37.1 None Pancreatic cancer 51 38.2 Associated with poor survival (85) Inversely associated with tumor-infiltrating CD8 cells 27.5 None
Volume 13, Issue 18
