A J Robert McGray

Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms

Adoptive cell therapy (ACT) has demonstrated curative potential in select cancers, but its translation to solid tumors such as ovarian cancer (OC) has been hindered by multiple factors, including tumor heterogeneity, immune exclusion, and a profoundly immunosuppressive tumor microenvironment. This review provides a comprehensive analysis of current ACT modalities, including tumor-infiltrating lymphocytes, T cell receptor-engineered, and chimeric antigen receptor-T cell therapies, as well as emerging approaches such as bispecific T cell engager (BiTE)-secreting T cells, dual-targeting platforms, and synthetic antigen receptors. We examine their application in OC and contextualize relevant findings using insights from other solid tumors. Key barriers, including limited T cell persistence, antigen escape, and T cell exhaustion, are explored alongside strategies to enhance efficacy through cytokine armoring, checkpoint modulation, metabolic reprogramming, and gene editing. We further highlight innovations in safety engineering, including logic-gated and self-regulating synthetic circuits, to mitigate toxicity and improve precision. Additional attention is given to the evolving role of allogeneic products and in vivo engineering as scalable solutions. Finally, we emphasize the critical value of integrating high-dimensional tools such as spatial transcriptomics, single-cell profiling, and machine learning to refine ACT design, identify biomarkers of response, and support patient selection and stratification. Collectively, these advances offer a roadmap for overcoming the unique immunologic barriers to ACT in OC and accelerating the development of more potent, durable, and personalized T cell-based strategies.

BiTE-secreting T cells rationally combine with PD-1 blockade and vaccine boosting to reshape antitumor immunity in ovarian cancer

Despite some clinical success, ovarian cancer (OC) patients rarely achieve durable benefit from current immunotherapies, suggesting a need for strategies that improve OC immune recognition. We previously reported that engineered T cells secreting folate receptor alpha (FRα)-targeted bispecific T cell engagers (FR-B T cells) elicit robust antitumor responses in OC, in part by engaging endogenous T cells. Here, we use clinical OC specimens and preclinical OC to evaluate FR-B T cells combined with PD-1 blockade. Assessing the tumor microenvironment during acute and prolonged FR-B T cell + anti-PD-1 responses revealed broad immune cell engagement/reorganization. Early CD8+ T cell-driven responses and myeloid cell influx were followed by accumulation of CXCL13-producing macrophages, activated B cells, and effector memory CD4+ T cells with durable response, hallmarks that were diminished with progressive disease. Resistant OC (characterized by FRα loss and metabolic reprogramming) emerged at disease relapse, suggesting a need to target additional vulnerabilities to extend responses. As FR-B T cells promoted epitope spreading beyond FRα, we employed a booster vaccine to enhance antitumor immunity, improving OC control. Our findings point to rationally combining FR-B T cells with PD-1 blockade in OC and an opportunity to apply personalized cancer vaccines to limit OC relapse.

BiTE secretion by adoptively transferred stem-like T cells improves FRα+ ovarian cancer control

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.

Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses

To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. IDO1 inhibition resulted in efficient blockade of the kynurenine pathway of tryptophan degradation and was accompanied by a metabolic adaptation that shunted tryptophan catabolism toward the serotonin pathway. This resulted in elevated nicotinamide adenine dinucleotide (NAD + ), which reduced T cell proliferation and function. Because NAD + metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD + on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD + -mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.