Low dose gemcitabine increases the cytotoxicity of human Vγ9Vδ2 T cells in bladder cancer cellsin vitroand in an orthotopic xenograft model

Abstract

Human γδT cell immunotherapy is well tolerated and has shown promising results in clinical trials; however, its antitumor efficacy is limited, including results in solid tumors. expanded γδT cell stimulated by zoledronic acid (ZOL) activates the γδT cell subpopulation of so called Vγ9Vδ2 T cells. To improve the clinical outcomes of Vγ9Vδ2 T cell (abbreviated as γδT cell here) immunotherapy, we aimed to increase the cytotoxicity of γδT cells by focusing on two issues: recognition of tumor cells by γδT cells and the effector (γδT cell)-to-target (tumor cell) (E/T) ratio.expanded γδT cells showed potent cytotoxicity against urinary bladder cancer (UBC) cells in assays. Combination treatment with standard anticancer agents showed that low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of γδT cells by upregulating the expression of and (), which are tumor-associated antigens recognized by γδT cells. These effects were abrogated by small interfering RNA-mediated knockdown of in UBC cells, suggesting that pre-exposing cancer cells to anticancer agents could be a promising strategy. A bladder instillation approach was used to increase the E/T ratio. The efficacy of-expanded γδT cell immunotherapy was examined in an orthotopic xenograft model. In Vivo Imaging System analysis revealed the potent cytotoxicity of weekly intravesical administration of γδT cells, and weekly gemcitabine pretreatment enhanced the cytotoxicity of γδT cells . In conclusion, intravesical γδT cell immunotherapy and combination therapy with low dose gemcitabine may be a promising strategy in UBC.

Trial watch: IDO inhibitors in cancer therapy

“…The Phase II study NCT03519256, enrolling subjects with high-risk, non-MIBC, is monitoring the therapeutic profile of BMS-986205 combined with two drugs already approved for some types of bladder cancer such as nivolumab [200][201][202][203][204] and the toll like receptor 2 (TLR2)/TLR4 agonist [205][206][207][208][209] bacillus Calmette-Guérin (BCG). [210][211][212] Along similar lines, the Phase III study NCT03661320 compared the efficacy, tolerability and safety of three therapeutic regimens for MIBC: neoadjuvant standard of care chemotherapy with cisplatin [213][214][215][216][217] and gemcitabine, 218,219 (NAC) versus NAC combined with nivolumab or nivolumab plus BMS-986205, followed by continuation of adjuvant immunotherapy (nivolumab with or without the IDO1 inhibitor) post radical cystectomy. 220 Additionally, four ongoing studies aim at elucidating the therapeutic profile of BMS-986205 in combination with nivolumab in patients affected by endometrial carcinoma or endometrial carcinosarcoma (NCT04106414), unresectable or metastatic HCC (NCT03695250), stage II to IV HNSCC (NCT03854032), as well as stage III or IV melanoma (NCT04007588).…”

“…The Phase II study NCT03519256, enrolling subjects with high-risk, non-MIBC, is monitoring the therapeutic profile of BMS-986205 combined with two drugs already approved for some types of bladder cancer such as nivolumab 200 - 204 and the toll like receptor 2 (TLR2)/TLR4 agonist 205 - 209 bacillus Calmette–Guérin (BCG). 210 – 212 Along similar lines, the Phase III study NCT03661320 compared the efficacy, tolerability and safety of three therapeutic regimens for MIBC: neoadjuvant standard of care chemotherapy with cisplatin 213 - 217 and gemcitabine, 218 , 219 (NAC) versus NAC combined with nivolumab or nivolumab plus BMS-986205, followed by continuation of adjuvant immunotherapy (nivolumab with or without the IDO1 inhibitor) post radical cystectomy. 220 …”

Editorial Comment to Effectiveness of the combination of vascular targeted photodynamic therapy and anti‐cytotoxic T‐lymphocyte‐associated antigen 4 in a preclinical mouse model of urothelial carcinoma

“…In this study, the authors used an ectopic model of subcutaneous cancer cell engraftment; however, orthotopic models of urinary bladder or renal pelvis might be preferable, as they better reflect the natural behavior of UC cells. This could be accomplished by transurethral administration of UC cancer cells, as we reported previously . As the results of this strategy showed that a combination of immunomodulatory agents and ICIs can yield successful results, various immunomodulatory agents have been investigated.…”

Preclinical orthotopic xenograft model of renal pelvis cancer in which cancer growth could be traced by an in vivo imaging system

“…We previously reported the appropriate orthotopic animal model of urinary bladder cancer, and investigated the efficacy and safety of intravesical cdT cells. 6 In that study, the UMUC3 cell line was transfected with the luciferase gene (Table S1). Luciferase signal-expressing UMUC3 cancer cells (UMUC3-luc) were established accordingly and used in the experiments shown below.…”

“…We previously reported the appropriate orthotopic animal model of urinary bladder cancer, and investigated the efficacy and safety of intravesical γδT cells . In that study, the UMUC3 cell line was transfected with the luciferase gene (Table S1).…”