The Factors Affecting Expansion of Reactive Tumor Infiltrating Lymphocytes (TIL) From Bladder Cancer and Potential Therapeutic Applications

Abstract

Tumor infiltrating lymphocytes (TIL) therapy was shown to provide durable objective response in patients with metastatic melanoma. As a fundamental first step to bring TIL therapy to clinical use, identification of patients whose tumors yield optimal numbers of reactive TIL is indispensable. We have previously shown that expansion of tumor reactive TIL from primary bladder tumors and lymph node metastases is feasible. Here, we performed TIL harvesting from additional surgical specimens (additional 31 primary tumors and 10 lymph nodes) to generate a heterogenous cohort of 53 patients with bladder cancer (BC) to evaluate the tumor characteristics that lead to tumor-reactive TIL expansion. Among a total of 53 patients, overall TIL growth from tumor samples were 37/53 (69.8%) and overall anti-tumor reactive TIL were 26/35 (74.3%). Mixed urothelial carcinoma is associated with higher anti-tumor reactivity of expanded TIL than pure urothelial carcinoma (89.5% vs. 56.3%, p=0.049). The anti-tumor reactivity of expanded TIL from primary tumors previously treated with BCG immunotherapy were lower (33.3% vs. 82.6%, p=0.027) although T-cell phenotype (CD3+, CD4+, CD8+, and CD56+) was similar regardless prior of BCG therapy. Addition of agonistic 4-1BB antibody in culture media with IL-2 improved the number of expanded TIL from primary tumors previously treated with BCG immunotherapy. There was no significant difference between basal and luminal subtype tumors in terms of viable and reactive TIL growth. Our study demonstrates that TIL expansion is feasible across all BC patients and BC subtypes, and we suggest that TIL therapy can be a reasonable treatment strategy for various manifestations of BC.

FGFBP1 as a potential biomarker predicting bacillus Calmette–Guérin response in bladder cancer

“…Although the mechanism concerning BCG action is still not completely understood, one main explanation is that BCG exposure to urothelium and bladder-resident macrophages elicits an inflammatory and immune response against tumoral cells (22)(23)(24)(25)(26). Moreover, an intrinsic or acquired immune resistance would be the possible resistance mechanism to BCG treatment.…”

Current State of Cell Therapies for Genitourinary Malignancies

“…Aydin et al 57 further investigated the factors influencing the growth of TILs from bladder tumors such as pretreatment history with bacillus Calmette-Guérin (BCG) and histological and molecular subtype. Of 53 samples, 37 samples produced TILs, and 20 samples were reactive to autologous tumor digest among 29 samples with available digest for coculture.…”

Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer

“…Due to the high mutational burden of both malignancies, ACT with TIL may induce similar responses in patients with bladder cancer ( 11 , 12 ). Feasibility studies of growing TIL from bladder tumors support that TIL can be expanded from bladder cancer patient samples ( 13 , 14 ). Additionally, previous work in murine models show that intravesical ACT with TIL is an effective method of treating smaller bladder tumors ( 15 ).…”