PT  - JOURNAL ARTICLE
AU  - McGray, A J Robert
AU  - Chiello, Jessie L
AU  - Tsuji, Takemasa
AU  - Long, Mark
AU  - Maraszek, Kathryn
AU  - Gaulin, Nicole
AU  - Rosario, Spencer R
AU  - Hess, Suzanne M
AU  - Abrams, Scott I
AU  - Kozbor, Danuta
AU  - Odunsi, Kunle
AU  - Zsiros, Emese
TI  - BiTE secretion by adoptively transferred stem-like T cells improves FRα+ ovarian cancer control
AID  - 10.1136/jitc-2023-006863
DP  - 2023 Jun 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e006863
VI  - 11
IP  - 6
4099  - http://jitc.bmj.com/content/11/6/e006863.short
4100  - http://jitc.bmj.com/content/11/6/e006863.full
SO  - J Immunother Cancer2023 Jun 01; 11
AB  - Background Cancer immunotherapies can produce complete therapeutic responses, however, outcomes in ovarian cancer (OC) are modest. While adoptive T-cell transfer (ACT) has been evaluated in OC, durable effects are rare. Poor therapeutic efficacy is likely multifactorial, stemming from limited antigen recognition, insufficient tumor targeting due to a suppressive tumor microenvironment (TME), and limited intratumoral accumulation/persistence of infused T cells. Importantly, host T cells infiltrate tumors, and ACT approaches that leverage endogenous tumor-infiltrating T cells for antitumor immunity could effectively magnify therapeutic responses.Methods Using retroviral transduction, we have generated T cells that secrete a folate receptor alpha (FRα)-directed bispecific T-cell engager (FR-B T cells), a tumor antigen commonly overexpressed in OC and other tumor types. The antitumor activity and therapeutic efficacy of FR-B T cells was assessed using FRα+ cancer cell lines, OC patient samples, and preclinical tumor models with accompanying mechanistic studies. Different cytokine stimulation of T cells (interleukin (IL)-2+IL-7 vs IL-2+IL-15) during FR-B T cell production and the resulting impact on therapeutic outcome following ACT was also assessed.Results FR-B T cells efficiently lysed FRα+ cell lines, targeted FRα+ OC patient tumor cells, and were found to engage and activate patient T cells present in the TME through secretion of T cell engagers. Additionally, FR-B T cell therapy was effective in an immunocompetent in vivo OC model, with response duration dependent on both endogenous T cells and FR-B T cell persistence. IL-2/IL-15 preconditioning prior to ACT produced less differentiated FR-B T cells and enhanced therapeutic efficacy, with mechanistic studies revealing preferential accumulation of TCF-1+CD39−CD69− stem-like CD8+ FR B T cells in the peritoneal cavity over solid tumors.Conclusions These findings highlight the therapeutic potential of FR-B T cells in OC and suggest FR-B T cells can persist in extratumoral spaces while actively directing antitumor immunity. As the therapeutic activity of infused T cell therapies in solid tumor indications is often limited by poor intratumoral accumulation of transferred T cells, engager-secreting T cells that can effectively leverage endogenous immunity may have distinct mechanistic advantages for enhancing therapeutic responses rates.Data are available upon reasonable request. Raw and processed RNA-seq data derived from FR-B 2/7 (n = 2) or FR-B 2/15 (n = 3) T cells supporting the findings of this study have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) under accession number GSE218730. All other data will be made available upon reasonable request made to the corresponding author.