Adoptive T cell therapy for ovarian cancer.

Although ovarian cancer patients typically respond to standard of care therapies, including chemotherapy and DNA repair inhibitors, the majority of tumors recur highlighting the need for alternative therapies. Ovarian cancer is an immunogenic cancer in which the accumulation of tumor infiltrating lymphocytes (TILs), particularly T cells, is associated with better patient outcome. Thus, harnessing the immune system through passive administration of T cells, a process called adoptive cell therapy (ACT), is a promising therapeutic option for the treatment of ovarian cancer. There are multiple routes by which tumor-specific T cell products can be generated. Dendritic cell cancer vaccines can be administered to the patients to induce or bolster T cell responses against tumor antigens or be utilized ex vivo to prime T cells against tumor antigens; these T cells can then be prepared for infusion. ACT protocols can also utilize naturally-occurring tumor-reactive T cells isolated from a patient tumor, known as TILs, as these cells often are heterogeneous in composition and antigen specificity with patient-specific cancer recognition. Alternatively, T cells may be sourced from the peripheral blood, including those that are genetically modified to express a tumor antigen-specific T cell receptor (TCR) or chimeric antigen receptor (CAR) to redirect their specificity and promote their activity against tumor cells expressing the target tumor antigen. Here, we review current ACT strategies for ovarian cancer and provide insights into advancing ACT therapy strategies for the treatment of ovarian cancer.

CD137+ tumor infiltrating lymphocytes predicts ovarian cancer survival.

OBJECTIVE: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy in the United States, and biomarkers of patient outcomes are limited. Data using immunohistochemical (IHC) analysis are mixed regarding whether and which tumor infiltrating lymphocytes (TILs) impact survival, and IHC does not adequately quantify rare cell populations, including CD137+ (4-1BB) tumor-reactive TILs. Our study investigates if a higher percentage of CD3+ CD137+ TILs is associated with improved overall survival (OS) in OC. METHODS: Flow cytometry was performed on viably banked OC digests. Chart review and statistical analysis were performed. Forty-seven patients were included, 40 of whom were diagnosed with high-grade serous ovarian carcinoma (HGSOC), papillary serous carcinoma, or undifferentiated histology. RESULTS: A high percentage of CD3+ CD137+ TILs correlated with improved OS (n = 40, r = 0.48, P = 0.0016). Subjects were divided into CD3+ CD137+ TIL high and low groups by the median. Subjects with high CD3+CD137+ TIL frequencies (>9.6%) had longer OS (Wilcoxon rank-sum test; P = 0.0032) and improved OS (logrank test; P = 0.007). Differences in CD3+ or CD3+ CD8+ TILs did not impact survival. CD3+ CD137+ TILs were predictive of OS regardless of germline mutation or debulking status. Analysis of subgroups including late stage HGSOC and late stage HGSOC with primary optimal cytoreduction indicated CD3+ CD137+ TILs correlated with improved OS after adjusting for age and PARP inhibitor use (P = 0.034 and P = 0.016, respectively). CONCLUSIONS: Prevalence of CD3+ CD137+ TILs in digested OC specimens is associated with improved OS, while general TIL markers are not. CD137 has the potential to be a novel biomarker for survival in OC.

A B7-H4-Targeting Antibody-Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression.

PURPOSE: Platinum and PARP inhibitors (PARPi) demonstrate activity in breast and ovarian cancers, but drug resistance ultimately emerges. Here, we examine B7-H4 expression in primary and recurrent high-grade serous ovarian carcinoma (HGSOC) and the activity of a B7-H4-directed antibody-drug conjugate (B7-H4-ADC), using a pyrrolobenzodiazepine-dimer payload, in PARPi- and platinum-resistant HGSOC patient-derived xenograft (PDX) models. EXPERIMENTAL DESIGN: B7-H4 expression was quantified by flow cytometry and IHC. B7-H4-ADC efficacy was tested against multiple cell lines in vitro and PDX in vivo. The effect of B7-H4-ADC on cell cycle, DNA damage, and apoptosis was measured using flow cytometry. RESULTS: B7-H4 is overexpressed in 92% of HGSOC tumors at diagnosis (n = 12), persisted in recurrent matched samples after platinum treatment, and was expressed at similar levels across metastatic sites after acquired multi-drug resistance (n = 4). Treatment with B7-H4-ADC resulted in target-specific growth inhibition of multiple ovarian and breast cancer cell lines. In platinum- or PARPi-resistant ovarian cancer cells, B7-H4-ADC significantly decreased viability and colony formation while increasing cell-cycle arrest and DNA damage, ultimately leading to apoptosis. Single-dose B7-H4-ADC led to tumor regression in 65.5% of breast and ovarian PDX models (n = 29), with reduced activity in B7-H4 low or negative models. In PARPi and platinum-resistant HGSOC PDX models, scheduled B7-H4-ADC dosing led to sustained tumor regression and increased survival. CONCLUSIONS: These data support B7-H4 as an attractive ADC target for treatment of drug-resistant HGSOC and provide evidence for activity of an ADC with a DNA-damaging payload in this population. See related commentary by Veneziani et al., p. 1434.

Diversity of neuropeptidergic modulation in decapod crustacean cardiac and feeding systems.

All nervous systems are multiply modulated by polypeptides. However, a bulk of transmitter and modulation research has historically focused on small molecule transmitters released at synaptic sites. The stomatogastric nervous system (controls digestive movements of the foregut) and cardiac nervous system of decapod crustaceans have long been used to understand the processes that underlie neuromodulation. The circuits governing the rhythmic output from these nervous systems are comprised of a relatively small number of identified neurons, and the details of these nervous systems are well-defined. Here we discuss recent research highlighting advances in our understanding of peptidergic modulation in these systems. In particular, we focus on our ability to identify specific signaling peptide sequences and relate their expression patterns to their physiological effects, as well as on the multiple sites within a pattern generator-effector system at which modulation takes place. Recent efforts have enabled us to understand how co-modulation by two or more peptides can generate surprising effects on circuit physiology and that modulation at different receptor sites can produce supra-additive effects. Finally, we examine the protective role modulation plays in making circuits robust to perturbations, in this case, changes in temperature.

Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes.

Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient costimulation in the tumor microenvironment can lead to T cell anergy and exhaustion resulting in poor anti-tumor activity. Here, we describe a chimeric costimulatory antigen receptor (CoStAR) comprised of FRα-specific scFv linked to CD28 and CD40 intracellular signaling domains. CoStAR signaling alone does not activate T cells, while the combination of TCR and CoStAR signaling enhances T cell activity resulting in less differentiated T cells, and augmentation of T cell effector functions, including cytokine secretion and cytotoxicity. CoStAR activity resulted in superior T cell proliferation, even in the absence of exogenous IL-2. Using an in vivo transplantable tumor model, CoStAR was shown to improve T cell survival after transfer, enhanced control of tumor growth, and improved host survival. CoStAR could be reliably engineered into TIL from multiple tumor indications and augmented TIL activity against autologous tumor targets both in vitro and in vivo. CoStAR thus represents a general approach to improving TIL therapy with synthetic costimulation.

The spectrum of MAPK-ERK pathway genomic alterations in gynecologic malignancies: Opportunities for novel therapeutic approaches.

OBJECTIVE: To investigate the incidence of MAPK/ERK pathway genomic alterations among patients with gynecologic malignancies. METHODS: We accessed the American Association of Cancer Research Genomics Evidence of Neoplasia Information Exchange publicly available dataset (v13.0). Patients with malignant tumors of the ovary, uterus, and cervix were identified. Following stratification by tumor site and histology, we examined the prevalence of MAPK/ERK pathway gene alterations (somatic mutation, and/or structural chromosome alterations). We included the following RAS-MAPK pathway genes known to be implicated in the dysregulation of the pathway; KRAS, NRAS, BRAF, HRAS, MAP2K1, RAF1, PTPN11, NF1, and ARAF. Data from the OncoKB database, as provided by cBioPortal, were utilized to determine pathogenic gene alterations. RESULTS: We identified a total of 10,233 patients with gynecologic malignancies; 48.2% (n = 4937) with ovarian, 45.2% (n = 4621) with uterine and 6.6% (n = 675) with cervical cancer respectively. The overall incidence of MAPK pathway gene alterations was 21%; the most commonly altered gene was KRAS (13%), followed by NF1 (7%), NRAS (1.3%), and BRAF (1.2%). The highest incidence was observed among patients with mucinous ovarian (71%), low-grade serous ovarian (48%), endometrioid ovarian (37%), and endometrioid endometrial carcinoma (34%). CONCLUSIONS: Approximately 1 in 5 patients with a gynecologic tumor harbor a MAPK/ERK pathway genomic alteration. Novel treatment strategies capitalizing on these alterations are warranted.

A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer.

We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study ( NCT01312376 /UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity.

Perspectives in Immunotherapy: meeting report from Immunotherapy Bridge (Naples, November 30th-December 1st, 2022).

The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors. These new approaches are focused on patients with an inadequate response to current treatments, with emerging evidence of improved responses in various cancers with new immunotherapy agents, often in combinations with existing agents. The use of cell therapies, drivers of immune response, and trends in immunotherapy were the focus of the Immunotherapy Bridge (November 30th-December 1st, 2022), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer.

The role of feedback and modulation in determining temperature resiliency in the lobster cardiac nervous system.

Changes in ambient temperature affect all biological processes. However, these effects are process specific and often vary non-linearly. It is thus a non-trivial problem for neuronal circuits to maintain coordinated, functional output across a range of temperatures. The cardiac nervous systems in two species of decapod crustaceans, Homarus americanus and Cancer borealis, can maintain function across a wide but physiologically relevant temperature range. However, the processes that underlie temperature resilience in neuronal circuits and muscle systems are not fully understood. Here, we demonstrate that the non-isolated cardiac nervous system (i.e., the whole heart: neurons, effector organs, intrinsic feedback systems) in the American lobster, H. americanus, is more sensitive to warm temperatures than the isolated cardiac ganglion (CG) that controls the heartbeat. This was surprising as modulatory processes known to stabilize the output from the CG are absent when the ganglion is isolated. One source of inhibitory feedback in the intact cardiac neuromuscular system is nitric oxide (NO), which is released in response to heart contractions. We hypothesized that the greater temperature tolerance observed in the isolated CG is due to the absence of NO feedback. Here, we demonstrate that applying an NO donor to the isolated CG reduces its temperature tolerance. Similarly, we show that the NO synthase inhibitor L-nitroarginine (LNA) increases the temperature tolerance of the non-isolated nervous system. This is sufficient to explain differences in temperature tolerance between the isolated CG and the whole heart. However, in an intact lobster, the heart and CG are modulated by an array of endogenous peptides and hormones, many of which are positive regulators of the heartbeat. Many studies have demonstrated that excitatory modulators increase temperature resilience. However, this neuromuscular system is regulated by both excitatory and inhibitory peptide modulators. Perfusing SGRNFLRFamide, a FLRFamide-like peptide, through the heart increases the non-isolated nervous system's tolerance to high temperatures. In contrast, perfusing myosuppressin, a peptide that negatively regulates the heartbeat frequency, decreases the temperature tolerance. Our data suggest that, in this nervous system, positive regulators of neural output increase temperature tolerance of the neuromuscular system, while modulators that decrease neural output decrease temperature tolerance.

TCRvß-CART therapy mediates high-precision targeting of malignant T-cell clones.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated with poor prognosis due to ineffective treatment options and high rates of relapse. The success of chimeric antigen receptor T-cell (CART) therapy for certain hematologic malignancies makes it an attractive treatment option for PTCLs. However, shared expression of potential target antigens by both malignant and healthy T cells poses a challenge. Current prospective CART approaches cause a high degree of on-target, off-tumor activity, resulting in fratricide during CART expansion, depletion of healthy T cells in vivo, and immune compromise in the patient. To limit off-tumor targeting, we sought to develop a CART platform specific for a given T-cell receptor vß (TCRvß) family that would endow CAR-modified T cells with the ability to mediate lysis of the clonal malignant population while preserving the majority of healthy T cells. Here, CAR constructs specific for multiple TCRvß family members were designed and validated. Our results demonstrate that TCRvß-family-specific CARTs (TCRvß-CARTs) recognize and kill TCRvß-expressing target cells. This includes specific self-depletion of the targeted cell subpopulation in the CART product and lysis of cell lines engineered to express a target TCRvß family. Furthermore, TCRvß-CARTs eliminated the dominant malignant TCRvß clone in 2 patient samples. Finally, in immunodeficient mice, TCRvß-CARTs eradicated malignant cells in a TCRvß-dependent manner. Importantly, the nontargeted TCRvß families were spared in all cases. Thus, TCRvß-CART therapy provides a potential option for high-precision treatment of PTCL with limited healthy T-cell depletion.

MEETING HIGHLIGHTS: THE THIRD MARIE SKLODOWSKA-CURIE SYMPOSIUM ON CANCER RESEARCH AND CARE AT ROSWELL PARK COMPREHENSIVE CANCER CENTER, BUFFALO, NY, SEPTEMBER 20-22, 2023.

Marie Sklodowska-Curie Symposia on Cancer Research and Care (MSCS-CRC) promote collaborations between cancer researchers and care providers in the United States, Canada and Central and Eastern European Countries (CEEC), to accelerate the development of new cancer therapies, advance early detection and prevention, increase cancer awareness, and improve cancer care and the quality of life of patients and their families. The third edition of MSCS-CRC, held at Roswell Park Comprehensive Cancer Center, Buffalo, NY, in September 2023, brought together 137 participants from 20 academic institutions in the US, Poland, Ukraine, Lithuania, Croatia and Hungary, together with 16 biotech and pharma entities. The key areas of collaborative opportunity identified during the meeting are a) creating of a database of available collaborative projects in the areas of early-phase clinical trials, preclinical development, and identification of early biomarkers; b) promoting awareness of cancer risks and efforts at cancer prevention; c) laboratory and clinical training; and d) sharing experience in cost-effective delivery of cancer care and improving the quality of life of cancer patients and their families. Examples of ongoing international collaborations in the above areas were discussed. Participation of the representatives of the Warsaw-based Medical Research Agency, National Cancer Institute (NCI) of the United States, National Cancer Research Institutes of Poland and Lithuania, New York State Empire State Development, Ministry of Health of Ukraine and Translational Research Cancer Center Consortium of 13 cancer centers from the US and Canada, facilitated the discussion of available governmental and non-governmental funding initiatives in the above areas.

Expression of inducible factors reprograms CAR-T cells for enhanced function and safety.

Despite the success of CAR-T cell cancer immunotherapy, challenges in efficacy and safety remain. Investigators have begun to enhance CAR-T cells with the expression of accessory molecules to address these challenges. Current systems rely on constitutive transgene expression or multiple viral vectors, resulting in unregulated response and product heterogeneity. Here, we develop a genetic platform that combines autonomous antigen-induced production of an accessory molecule with constitutive CAR expression in a single lentiviral vector called Uni-Vect. The broad therapeutic application of Uni-Vect is demonstrated in vivo by activation-dependent expression of (1) an immunostimulatory cytokine that improves efficacy, (2) an antibody that ameliorates cytokine-release syndrome, and (3) transcription factors that modulate T cell biology. Uni-Vect is also implemented as a platform to characterize immune receptors. Overall, we demonstrate that Uni-Vect provides a foundation for a more clinically actionable next-generation cellular immunotherapy.

Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma.

Astatine-211-parthanatine ([211At]PTT) is an alpha-emitting radiopharmaceutical therapeutic that targets poly(adenosine-diphosphate-ribose) polymerase 1 (PARP1) in cancer cells. High-risk neuroblastomas exhibit among the highest PARP1 expression across solid tumors. In this study, we evaluated the efficacy of [211At]PTT using 11 patient-derived xenograft (PDX) mouse models of high-risk neuroblastoma, and assessed hematological and marrow toxicity in a CB57/BL6 healthy mouse model. We observed broad efficacy in PDX models treated with [211At]PTT at the maximum tolerated dose (MTD 36 MBq/kg/fraction x4) administered as a fractionated regimen. For the MTD, complete tumor response was observed in 81.8% (18 of 22) of tumors and the median event free survival was 72 days with 30% (6/20) of mice showing no measurable tumor >95 days. Reversible hematological and marrow toxicity was observed 72 hours post-treatment at the MTD, however full recovery was evident by 4 weeks post-therapy. These data support clinical development of [211At]PTT for high-risk neuroblastoma.

Pragmatic evaluation of methods for retrieving unpublished information on comparator interventions in a systematic review of smoking cessation trials.

OBJECTIVE: Reporting of the content and delivery characteristics of comparator interventions in published articles is often incomplete. This study examines the feasibility and validity of two methods for collecting additional information on comparator interventions from trial authors. METHODS & MEASURES: In a systematic review of smoking cessation trials (IC-Smoke), all trial authors were asked to send unpublished comparator intervention materials and complete a specially-developed comparator intervention checklist. All published and additionally obtained information from authors were coded for behaviour change techniques (BCTs) and other characteristics (type of comparator, provider, provider training, delivery mode and treatment duration). To assess representativeness, we assessed the amount of additional information obtained from trial authors compared with the amount that was published. We examined known-group and convergent validity of comparator intervention data when using only published or also unpublished information. RESULTS: Additional information were obtained from 91/136 (67%) of trial authors. Representativeness, known-group and convergent validity improved substantially based on the data collected by means of the comparator intervention checklist, but not by requesting authors to send any existing comparator materials. CONCLUSIONS: Requesting authors for unpublished comparator intervention data, using specially-developed checklists and unpublished materials, substantially improves the quality of data available for systematic reviews.

Structural variation between neuropeptide isoforms affects function in the lobster cardiac system.

Neuronal responses to peptide signaling are determined by the specific binding of a peptide to its receptor(s). For example, isoforms of the same peptide family can drive distinct responses in the same circuit by having different affinities for the same receptor, by having each isoform bind to a different receptor, or by a combination of these scenarios. Small changes in peptide composition can alter the binding kinetics and overall physiological response to a given peptide. In the American lobster (Homarus americanus), native isoforms of C-type allatostatins (AST-Cs) usually decrease heartbeat frequency and alter contraction force. However, one of the three AST-C isoforms, AST-C II, drives a cardiac response distinct from the response elicited by the other two. To investigate the aspects of the peptide that might be responsible for these differential responses, we altered various features of each peptide sequence. Although the presence of an amide group at the end of a peptide sequence (amidation) is often essential for determining physiological function, we demonstrate that C-terminal amidation does not dictate the AST-C response in the lobster cardiac system. However, single amino acid substitution within the consensus sequence did account for many of the differences in specific response characteristics (e.g. contraction frequency or force).

Epigenetic state determines inflammatory sensing in neuroblastoma.

Immunotherapy has revolutionized cancer treatment, but many cancers are not impacted by currently available immunotherapeutic strategies. Here, we investigated inflammatory signaling pathways in neuroblastoma, a classically "cold" pediatric cancer. By testing the functional response of a panel of 20 diverse neuroblastoma cell lines to three different inflammatory stimuli, we found that all cell lines have intact interferon signaling, and all but one lack functional cytosolic DNA sensing via cGAS-STING. However, double-stranded RNA (dsRNA) sensing via Toll-like receptor 3 (TLR3) was heterogeneous, as was signaling through other dsRNA sensors and TLRs more broadly. Seven cell lines showed robust response to dsRNA, six of which are in the mesenchymal epigenetic state, while all unresponsive cell lines are in the adrenergic state. Genetically switching adrenergic cell lines toward the mesenchymal state fully restored responsiveness. In responsive cells, dsRNA sensing results in the secretion of proinflammatory cytokines, enrichment of inflammatory transcriptomic signatures, and increased tumor killing by T cells in vitro. Using single-cell RNA sequencing data, we show that human neuroblastoma cells with stronger mesenchymal signatures have a higher basal inflammatory state, demonstrating intratumoral heterogeneity in inflammatory signaling that has significant implications for immunotherapeutic strategies in this aggressive childhood cancer.

PTEN Loss and BRCA1 Promoter Hypermethylation Negatively Predict for Immunogenicity in BRCA-Deficient Ovarian Cancer.

PURPOSE: Ovarian cancers can exhibit a prominent immune infiltrate, but clinical trials have not demonstrated substantive response rates to immune checkpoint blockade monotherapy. We aimed to understand genomic features associated with immunogenicity in BRCA1/2 mutation-associated cancers. MATERIALS AND METHODS: Using the Cancer Genome Atlas whole-exome sequencing, methylation, and expression data, we analyzed 66 ovarian cancers with either germline or somatic loss of BRCA1/2 and whole-exome sequencing, immunohistochemistry, and CyTOF in 20 ovarian cancers with germline BRCA1/2 pathogenic variants from Penn. RESULTS: We found two groups of BRCA1/2 ovarian cancers differing in their immunogenicity: (1) 37 tumors significantly enriched for PTEN loss (11, 30%) and BRCA1 promoter-hypermethylated (10, 27%; P = .0016) and (2) PTEN wild-type (28 of 29 tumors) cancers, with the latter group having longer overall survival (OS; P = .0186, median OS not reached v median OS = 66.1 months). BRCA1/2-mutant PTEN loss and BRCA1 promoter-hypermethylated cancers were characterized by the decreased composition of lymphocytes estimated by gene expression (P = .0030), cytolytic index (P = .034), and cytokine expression but higher homologous recombination deficiency scores (P = .00013). Large-scale state transitions were the primary discriminating feature (P = .001); neither mutational burden nor neoantigen burden could explain differences in immunogenicity. In Penn tumors, PTEN loss and high homologous recombination deficiency cancers exhibited fewer CD3+ (P = .05), CD8+ (P = .012), and FOXP3+ (P = .0087) T cells; decreased PRF1 expression (P = .041); and lower immune costimulatory and inhibitory molecule expression. CONCLUSION: Our study suggests that within ovarian cancers with genetic loss of BRCA1/2 are two subsets exhibiting differential immunogenicity, with lower levels associated with PTEN loss and BRCA hypermethylation. These genomic features of BRCA1/2-associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic.

Systematic analysis of CD39, CD103, CD137, and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs.

The detection of tumor-specific T cells in solid tumors is integral to interrogate endogenous antitumor responses and to advance downstream therapeutic applications. Multiple biomarkers are reported to identify endogenous tumor-specific tumor-infiltrating lymphocytes (TILs), namely CD137, PD-1, CD103, and CD39; however, a direct comparison of these molecules has yet to be performed. We evaluated these biomarkers in primary human ovarian tumor samples using single-cell mass cytometry to compare their relative phenotypic profiles, and examined their response to autologous tumor cells ex vivo. PD-1+ , CD103+ , and CD39+ TILs all contain a CD137+ cell subset, while CD137+ TILs highly co-express the aforementioned markers. CD137+ TILs exhibit the highest expression of cytotoxic effector molecules compared to PD-1+ , CD103+ , or CD39+ TILs. Removal of CD137+ cells from PD-1+ , CD103+ , or CD39+ TILs diminish their IFN-γ secretion in response to autologous tumor cell stimulation, while CD137+ TILs maintain high HLA-dependent IFN-γ secretion. CD137+ TILs exhibited an exhausted phenotype but with CD28 co-expression, suggesting possible receptiveness to reinvigoration via immune checkpoint blockade. Together, our findings demonstrate that the antitumor abilities of PD-1+ , CD103+ , and CD39+ TILs are mainly derived from a subset of CD137-expressing TILs, implicating CD137 as a more selective biomarker for naturally occurring tumor-specific TILs.

Humanized Patient-Derived Xenograft Models of Ovarian Cancer.

In vivo modeling of cancer is a critical step in testing novel therapeutic strategies to advance patient care. Here we describe how to develop a humanized patient-derived xenograft (PDX) model of ovarian cancer that uses orthotopically transplanted patient ovarian tumors with autologous transfer of expanded tumor infiltrating T cells (TILs) as a model that can be utilized to test immunomodulating therapeutics in vivo.