P1, N=0, Withdrawn, Sichuan Baili Pharmaceutical Co., Ltd. | N=29 --> 0 | Recruiting --> Withdrawn

P1, N=29, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

P1, N=29, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

Expansions ranged from ~1,000 to 17,000 fold, which mainly depended on the starting cell number. In summary, these data provide proof of concept for the isolation and expansion of antigen-reactive T cells from tumor digest or peripheral blood in a closed, automated manner using the GMP-compliant CliniMACS Prodigy platform, allowing for the desired efficiency, simplicity and automated production of cellular products for ACT therapies against cancer.

Moreover, DuoBody-PD-L1×4-1BB exhibits anti-tumor activity and induces memory immune responses in vivo. DuoBody-PD-L1×4-1BB is currently being evaluated in patients with advanced solid tumors in a first-in-human clinical trial (NCT03917381).

In summary, we combined a TCR of high natural anti-tumor reactivity for an HLA-A2-restricted PRAME- epitope with a chimeric PD1-41BB switch receptor that enhances T cell function and counteracts checkpoint- mediated dysfunction. This is a promising strategy to develop more effective TCR-T drug products for the treatment of solid cancers.

These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological "cold tumor" to "hot tumor".

P2, N=44, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2021 --> Mar 2022 | Trial primary completion date: Apr 2021 --> Sep 2021

The authors' novel bicistronic CD19/CD20 CAR T cells demonstrate improved anti-tumor efficacy in response to dual antigen stimulations. These data provide optimism that this novel bicistronic CAR construct can improve treatment outcomes in patients with relapsed/refractory B cell malignancy.

CD28 superiority was also demonstrated with HER2-specific CAR T cells (targeting ovarian carcinoma xenografts). Our findings encourage incorporating CD28 signaling into CAR design for adoptive T cell treatment of solid tumors.

P1b, N=24, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=99 --> 24

In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.

No abstract available

Natural killer cells expressing an anti-CD137 chimeric antigen receptor specifically kill CD137-expressing RMS cells. Our study implicates ectopic CD137 expression as a pathogenesis mechanism in RMS, and it demonstrates that CD137 may be a novel target for immunotherapy of RMS.

This study aimed to screen the expression profiles of circRNA, miRNA, and mRNA of ovarian cancer cells induced by Torin 1 (10 µM)...CircRAB11FIP1 bound to desmocollin 1to facilitate its interaction with ATG101...In general, this study demonstrated that circRAB11FIP1 regulated ATG7 and ATG14 by sponging miR-129. The data suggested that circRAB11FIP1 might serve as a candidate biomarker for EOC diagnosis and treatment.

By stimulating CD40 and 4-1BB, the cold tumor milieu can be converted to a hot milieu with increased T cells and activation markers. Data will be presented from clinical trials using an oncolytic virus expressing TMZCD40L and 4-1BBL

This study emphasizes the difficulties in recruiting patients for cell therapy trials, though NKAE cell infusion is safe and feasible. However, we cannot draw any conclusions regarding efficacy because of the small number of included patients and insufficient biological markers.

We found that the low TNFRSF9 expression level in Tregs was associated with enhanced overall survival rate and response to anti-PD-1 immunotherapy in patients with NSCLC, proposing that TNFRSF9 promotes immune suppressive activity of Tregs in tumor. Collectively, these results demonstrated that integrative transcriptome and network analysis can facilitate the discovery of functional markers of tumor-specific immune cells to develop novel therapeutic targets and biomarkers for boosting cancer immunotherapy.

Strikingly, we report the induction of a systemic antitumor immune response including tumor antigen spread by local MVA-TAA-4-1BBL treatment which controlled tumor growth at distant, untreated lesions and protected against local and systemic tumor rechallenge. In all cases, 4-1BBL adjuvanted MVA was superior to MVA.Conclusion Intratumoral 4-1BBL-armed MVA immunotherapy induced a profound reactivation and expansion of potent tumor-specific CD8 T cells as well as favorable proinflammatory changes in the tumor microenvironment, leading to elimination of tumors and protective immunological memory.

P1, N=42, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

In conclusion, TIL products from RCC lesions contain tumor-reactive Tcells. Their restricted tumor-specific cytokine production requires further investigation of immunosuppressive factors in RCC and subsequent optimization of RCC-derived TIL culture conditions.

 Overall, these pre-clinical data show that CAR T cells redirected against GD2 antigen may be considered as an alternative therapeutic option for selected GD2 highly-expressing pediatric sarcomas patients.

 Overall, these pre-clinical data show that CAR T cells redirected against GD2 antigen may be considered as an alternative therapeutic option for selected GD2 highly-expressing pediatric sarcomas patients.

 Overall, these pre-clinical data show that CAR T cells redirected against GD2 antigen may be considered as an alternative therapeutic option for selected GD2 highly-expressing pediatric sarcomas patients.

 Overall, these pre-clinical data show that CAR T cells redirected against GD2 antigen may be considered as an alternative therapeutic option for selected GD2 highly-expressing pediatric sarcomas patients.

P1b, N=45, Active, not recruiting, Pieris Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

P1b, N=45, Recruiting, Pieris Pharmaceuticals, Inc. | Suspended --> Recruiting | Trial completion date: Feb 2021 --> Jul 2021 | Trial primary completion date: Dec 2020 --> May 2021

While poor T-cell activation and severe T-cell exhaustion appear to be limiting factors for checkpoint blockade in GBM, 4-1BB agonism obviates these limitations and produces long-term survival when combined with anti-PD-1 therapy. Furthermore, this combination therapy is limited by TIL 4-1BB expression, but not by the intracranial compartment, and therefore may be particularly well-suited to GBM.

Finally, we demonstrated in humanized mouse models that these effector CAR T cells exert low or no cytotoxicity against various subsets of normal cells with low CD123 expression, indicating a potentially low on-target/off-tumor toxicity effect. Collectively, our data support the further evaluation for clinical assessment of CD28/4-1BB CD123 CAR T cells in BPDCN neoplasm.

In particular, 4-1BB stimulation in combination with PSMAxCD3 enhanced T-cell activation and proliferation, boosted efficacy against larger tumors, and induced T-cell memory, leading to durable antitumor responses. The combination of CD3 bispecific antibodies and anti-4-1BB costimulation represents a therapeutic approach for the treatment of solid tumors.

A+U in combination with RICE was safe and tolerable as a salvage regimen for ASCT-eligible patients with R/R DLBCL, demonstrating a promising CR rate of 50%. Further evaluation of checkpoint modulation in combination with salvage chemotherapy is needed to determine the optimal approach.

Severely exhausted PD-1 CD39 CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers.

Consistent with the enhanced proliferation and cytotoxicity in vitro, this new structure of CAR-T cells exhibited robust persistence and anti-tumor activity in a mouse xenograft lymphoma model. This work provides evidence for a new strategy to optimize the function of CAR-T against lymphoma.

Furthermore, chPD1-Dap10 and -41BB receptors induced a memory precursor phenotype, had enhanced persistence in vivo, and superior therapeutic efficacy in murine models of T cell lymphoma and melanoma compared to chPD1-CD28 or chPD1-GITR expressing T cells. Therefore, each costimulatory domain induces differential effects in CAR-expressing T cells and inclusion of Dap10 or 4-1BB costimulatory domains may induce a preferential cytokine profile and differentiation for cancer therapy.

However, higher TNFRSF9 signature was correlated with larger tumor size shrinkage (p = .003) and better progression-free survival (p = .012) in patients treated with nivolumab but not everolimus. TNFRSF9 CD8 T cells, which possessed both exhaustion and effector phenotype, were identified as an adverse prognosticator in ccRCC. These cells enrichment was associated with better immunotherapy response which indicated these cells potentially be crucial in immunotherapy.

In this study we showed that serum IgM-RF can be regarded as predictive factor for the development of early progression and prognostic factor of a reduced progression-free survival and overall-survival in anti-PD-1 treated NSCLC patients. The ability of IgM-RF to bind naïve and central memory T-cells and impair their migration could make account for the reduction of the tumor-reactive CD137 T-cells population that may cause a non-effectiveness of these T-cells targeting drugs.

Inhibition of VEGFR2 by siRNA or XL184 (cabozantinib) and inhibition of downstream signaling by LY294002 (inhibits AKT activation) and L-NAME (eNOS inhibitor) remarkably abolished proangiogenic effects of CD137 signaling both in vitro and ex vivo...In conclusion, activation of CD137 signaling promoted sprouting angiogenesis by increased VEGFA secretion and the VEGFR2/Akt/eNOS pathway. These findings provide a basis for stabilizing intraplaque angiogenesis through VEGFR2 intervatioin, as well as cancer treatment via combination of CD137 agonists and specific VEGFR2 inhibitors.

RO7227166, a CD19 targeted 4-1BBL (CD137) costimulatory agonist has shown synergistic anti‑tumor activity when combined with glofitamab in preclinical models (fig 1). The maximum duration of the study for each participant will be up to 24 months in Part I (excluding survival follow-up) and up to 18 months in Part II and Part III. Tumor biopsies and peripheral blood biomarker analyses will be used to demonstrate MoA and proof of concept of an off the shelf flexible combination option providing signals 1 and 2.

PRAME-specific T cells for adoptive immunotherapy were enriched from healthy donor mononuclear cells. The products were oligoclonal, exhibited Th1 phenotype and produced multiple cytokines.

4-1BB stimulation augmented expansion kinetics and favored CD8 occurrence. In conclusion, TIL expansion from sarcoma is feasible and expanded TILs highly express LAG3 and comprise multifunctional tumor-reactive T-cells.

These preclinical studies support our approach to enhance the clinical efficacy of TCR-T therapies of solid tumors using the chimeric PD1-41BB switch receptor. Subsequent in vivo studies and safety evaluations will pave the way for clinical use of PD1-41BB in adoptive T cell therapy.