Is Immune Checkpoint Blockade Altered By Specific Gene Therapy Directed Against Bcl-2?

Abstract

Antisense oligonucleotides (oligos) have been administered against prostatic LNCaP cells in both in vivo and in vitro models. In spite of advances in early detection, the treatment of prostate cancer has not improved and it is estimated that 233,000 new cases will be diagnosed and 29,450 men will die from it this year in the United States. Gene therapy and immune checkpoint blockade could provide some improvement. However, our studies indicate that gene therapy employing oligos directed towards bcl-2 (in LNCaP cells) frequently are compensated for by altered regulation of apoptosis, increased androgen sensitivity and enhanced oncogene activity. In addition, we found that certain oligo conformations induce interferon, enhance cell surface antigen expression [prostate specific membrane antigen (PSMA)] and potentially increase tumor recognition and targeting by the immune system. We hypothesized that immunologic recognition is an additional pathway for compensation which follows suppressive bcl-2 treatment and suggest that this type of gene therapy could influence proteins associated with immune checkpoint blockade now the “standard for care” treatment of melanoma and currently being evaluated for kidney and other solid tumors (including the prostate). Therefore, markers targeted by these new agents should be evaluated to identify changes in expression produced by previous therapy.

Keywords: Antisense; Prostate cancer; Therapy