Improved Tumor Control Research Articles

Neoadjuvant immune checkpoint blockade in resectable hepatocellular carcinoma: A systematic review and meta-analyisis.

590 Background: Hepatocellular carcinoma (HCC) presents a significant therapeutic challenge due to its high recurrence rates after curative-intent resection. Neoadjuvant immune checkpoint blockade (ICB) has emerged as a promising strategy to improve tumor control by modulating the immune microenvironment prior to surgery. This systematic review and meta-analysis aim to assess the safety and efficacy of neoadjuvant ICB in improving clinical outcomes for patients with resectable HCC. Methods: A systematic search of PubMed, EMBASE, and Cochrane databases was conducted to identify clinical trials examining neoadjuvant ICB in resectable HCC. Primary endpoints included pathological complete response (pCR), major pathological response (mPR), overall response rate (ORR), and grade 3-4 treatment-related adverse events (TRAE). Prespecified subgroup analyses were conducted for studies combining ICB with tyrosine kinase inhibitors (TKIs) or dual ICB therapies. Pooled proportions were calculated using a random-effects model via the R package "meta." Inter-study heterogeneity was assessed using the I² statistic and test for subgroup differences were conducted. Results: Out of 1,321 studies screened, 14 clinical trials involving 252 patients with resectable HCC were included. Most studies were phase II trials (57%), and patient median age ranged from 57.5 to 68.0 years, with 88.3% of patients being male. The pooled prevalence of mPR was 32% (95% CI, 24–42%; I² = 9%)while pCR was achieved in 24% (95% CI, 17–34%; I² = 29%)of patients. The ORR was 27% (95% CI, 18–39%; I² = 49%), and severe adverse events (grade 3-4 TRAE) had a pooled prevalence of 24% (95% CI, 17–34%; I² = 16%). Subgroup analysis of trials combining ICB with TKIs showed an ORR 34% (95% CI, 20–55%; I² = 60%), an mPR rate of 27% (95% CI, 19–40%; I² = 0%), and a pCR rate of 20% (95% CI, 14–30%; I² = 0%). Dual ICB therapies demonstrated a higher mPR rate of 42% (95% CI, 26–67%; I² = 16%) and a pCR rate of 41% (95% CI, 29–59%; I² = 29%), but were associated with a higher incidence of severe TRAE (41%; 95% CI, 29–60%; I² = 0%). Conclusions: Neoadjuvant ICB demonstrates promising efficacy in resectable HCC, particularly when combined with TKIs or dual ICB therapies. While dual ICB enhances pathological response rates, it is associated with higher rates of severe TRAE. These results highlight the need of further studies to optimize combination strategies that balance efficacy and safety for patients with resectable HCC.

A Systematic Review of Indications and Clinical Outcomes of Electrochemotherapy in Pancreatic Ductal Adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult cancers to treat, with a dismal 5-year survival rate of only 8–10%. This challenging prognosis highlights the urgent need for innovative therapeutic approaches to improve outcomes for patients with PDAC. Electrochemotherapy (ECT), which enhances intracellular chemotherapeutic uptake via electric pulses, has been explored for resectable, borderline resectable (BR), locally advanced (LA), recurrent, and metastatic PDAC, either as a complement to conventional treatments or as an alternative when these are not feasible or effective, offering possible benefits in symptomatic palliation and local tumor control. Methods: A systematic review was performed in accordance with PRISMA guidelines for studies assessing the efficacy of ECT in PDAC. After searching Embase, PubMed/MEDLINE, Scopus, and Web of Science, five studies with a combined total of 43 patients in various disease stages were identified. Results: ECT showed promise in improving tumor control, alleviating cancer-related pain, and improving quality of life. One study noted a trend towards tumor size reduction of 8.3% at one-month and 16.1% at six-months follow-up (p = 0.211 and p = 0.315), although these findings were derived from studies conducted without specific comparative control groups. Severity of complication was mainly mild (Clavien–Dindo I-II), while severe complications occurred in only 2.3% of patients. Median overall survival was reported in two studies as 8 months (range 2–19) and 11.5 months (range 1–74). ECT showed efficacy for symptom management, with 60% of patients reporting reduced pain/discomfort and 40% showing enhanced quality of life in one study, while another reported pain scores as decreasing from 6 to 3 at one month and to 2 at six months. Conclusions: ECT appears to be a new promising and safe adjunct treatment modality in PDAC management across different disease stages, with potential benefits in tumor control, cancer-related pain reduction, and quality of life. Further studies are warranted to validate these findings and identify patients who could benefit most.

Abstract B010: Interim report of Phase I study of window-of-opportunity fractionated stereotactic radiotherapy combined with checkpoint blockade prior to surgical resection for newly diagnosed glioblastoma

Abstract Background: Preclinical studies with transplanted GL261 glioma in mouse brain treated with radiosurgery and checkpoint blockade showed dramatic improvement of tumor cure and prolonged survival, associated with activated macrophage infiltration in the tumor site. We perform phase I study in patients with glioblastoma to assess safety and local tumor response by combined radiosurgery and checkpoint inhibitor given during window-of-opportunity prior to surgical resection, and progression-free survival and overall survival. Method and Procedure: Biopsy-proven WHO grade 4 glioblastoma patients were enrolled to the study (NCT05423210). Patients were treated with two doses of intravenous Atezolizumab at the beginning and at the end of the two-week period, concomitantly with fractionated radiosurgery (8 Gy x 4 to the grossly enhancing tumor) over 4 days during the course of 2 weeks. Maximal safe surgical resection was subsequently performed within 2 weeks from completion of radiosurgery. Adjuvant radiation 50 Gy over 5 weeks and Temozolomide were given as per standard treatment of GBM along with continuation of Atezolizumab until unacceptable toxicity or tumor progression. The initial biopsy specimen and surgical specimen were collected for laboratory examination of immune profiles. Results: The study plans to enroll total 12 histologically confirmed CNS WHO Grade 4 GBM patients also planned for surgical resection. Six patients were enrolled after consenting so far. There was no grade 3 or 4 toxicity from the window-of-opportunity combination treatment, all 6 patients successfully completing the treatment. Three patients reported fatigue and two patients had skin rash. There was one patient experiencing metallic taste. At present, five patients survive progression-free at 25, 18, 16 and 6 months since the treatment. An unanticipated finding is that there was significantly less intraoperative bleeding in the surgical field than usual brain tumor surgery. Conclusion: Preoperative fractionated radiosurgery and Atezolizumab was well tolerated so far, and appear to improve tumor control. We continue enroll the patients. Lab study of immune cell profile is underway. Citation Format: Samuel Ryu, Alexander Stessin, Charles Mikell, Agnieszka Kowalska, Roberta Seidman, Steven West, Kartik Mani. Interim report of Phase I study of window-of-opportunity fractionated stereotactic radiotherapy combined with checkpoint blockade prior to surgical resection for newly diagnosed glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B010.

Abstract A011: Activity of antibody-drug conjugates with radiation in preclinical bladder cancer models

Abstract Antibody-drug conjugates (ADCs) are transforming the treatment landscape in metastatic bladder cancer, but the role of ADCs in localized disease is uncertain. Radiation is a central component of trimodality therapy (TMT), a curative-intent treatment approach for muscle-invasive bladder cancer (MIBC) that includes concurrent radiation and cytotoxic chemotherapy. We investigated the safety and efficacy of combining novel ADCs with radiation in preclinical bladder cancer models. We observed additive cytotoxicity in vitro, and the combination of ADCs with conformal fractionated radiation was well-tolerated and resulted in improved tumor control compared to either agent alone in vivo. We also assessed the impact of DNA repair pathway alterations commonly observed in bladder tumors on sensitivity to ADCs alone and in combination with radiation and DNA repair targeted agents. Homologous recombination (HR) deficiency modestly sensitized bladder cancer cells to MMAE, the payload of the ADC enfortumab vedotin (EV), and potently sensitized cells to govitecan, the payload of the ADC sacitumuzab govitecan (SG). Conversely, nucleotide excision repair (NER) deficiency did not sensitize cells to either MMAE or govitecan. The combination of govitecan and PARP inhibition resulted in synergistic cell killing independent of HR or NER status. Together these data provide preclincal support for clinical efforts to combine ADCs with radiation in MIBC and identify rationale combination therapy approaches. Citation Format: Yuzhen Zhou, Surish Shanmugam, Vincent D'Andrea, Isabella Stelter, Dag Stormoen, Rea Chroneos, Timothy Hanlon, Ilana Epstein, Raie Bekele, William Anderson, Zoltan Szallasi, Joaquim Bellmunt, Kent Mouw. Activity of antibody-drug conjugates with radiation in preclinical bladder cancer models. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A011.

Abstract B032: Concurrent mutant KRAS inhibition and Stereotactic Body Radiation Therapy (SBRT) for preclinical KRASG12D-Driven Pancreatic Ductal Adenocarcinoma (PDAC) treatment

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is known for its extensive intrinsic and acquired resistance to standard of care therapies. With the KRASG12D mutation being a key driver, MRTX1133, a selective small molecule KRASG12D inhibitor, has demonstrated superior anti-tumor efficacy in preclinical PDAC models. However, tumor resistance to MRTX1133 is expected to occur inevitably. We hypothesize that combining MRTX1133 with stereotactic body radiation therapy (SBRT) can enhance local tumor control and minimize tumor recurrence after treatment. Methods: C57Bl/6J mice orthotopically transplanted with luciferase-tagged mouse KPC PDAC cells (KrasG12D; Trp53R172H; Pdx1-Cre) were assigned to 4 treatment groups: (1) vehicle, (2) SBRT (8 Gy x 5), (3) MRTX1133 (30 mg/kg I.P. BID), and (4) SBRT + MRTX1133. Tumor progression was monitored with IVIS luciferase imaging, and survival data were collected and analyzed using a Log-rank test. At the study endpoint, tumors as well as normal tissues were collected for histological analysis to evaluate immune cell infiltration, tumor proliferation and differentiation, and normal tissue toxicity. Results: SBRT + MRTX1133 combination therapy significantly enhanced local tumor control and prolonged mouse survival when compared to either MRTX1133 or SBRT alone. The median survival in the combination group exceeded 120 days, with significantly reduced tumor burden, suggesting a synergistic effect between SBRT and MRTX1133 in suppressing KPC tumor progress in vivo. Conclusion: Our findings demonstrate that MRTX1133 combined with SBRT improves tumor control and overall survival in a preclinical KRASG12D-driven PDAC tumor model. This combination strategy has the potential for clinical translation, offering a promising therapeutic approach to overcome resistance and improve outcomes in PDAC patients. Citation Format: Tianyu Wang, Jasper R Chen, Vincent Bernard Pagan, Liang Wang, Youming Guo, Ling Xia, Pankaj K. Singh, Dadi Jiang, Albert Koong. Concurrent mutant KRAS inhibition and Stereotactic Body Radiation Therapy (SBRT) for preclinical KRASG12D-Driven Pancreatic Ductal Adenocarcinoma (PDAC) treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B032.

Advances in Radiation Oncology in Soft Tissue Sarcoma.

To review recent advances with radiation therapy (RT) for soft tissue sarcomas (STS). Newer data showcases hypofractionated preoperative RT for soft tissue sarcomas treated with surgery to be safe and effective, however, long-term follow up data is pending. Hypofractionated and dose-escalated RT in patients with unresectable STS is also being studied, for which we remain optimistic given advances in RT planning approaches. SFRT may also be considered in select cases to improve tumor control outcomes. Finally, for patients requiring high doses of RT adjacent to critical structures, re-irradiation, and to minimize risk of secondary malignancy in our younger population, particle therapy may be beneficial. We summarize a number of recent advances in RT for STS that can benefit patients with localized disease as well as for patients with advanced disease.

PKCδ germline variants and genetic deletion in mice augment antitumor immunity through regulation of myeloid cells.

Based on the notion that hypomorphic germline genetic variants are linked to autoimmune diseases, we reasoned that novel targets for cancer immunotherapy might be identified through germline variants associated with greater T-cell infiltration into tumors. Here, we report that while investigating germline polymorphisms associated with a tumor immune gene signature, we identified PKCδ as a candidate. Genetic deletion of PKCδ in mice resulted in improved endogenous antitumor immunity and increased efficacy of anti-PD-L1. Single-cell RNA sequencing revealed myeloid cell expression of Prkcd, and PKCδ deletion caused a shift in macrophage gene expression from an M2-like to an M1-like phenotype. Conditional deletion of PKCδ in myeloid cells recapitulated improved tumor control that was augmented further with anti-PD-L1. Analysis of clinical samples confirmed an association between PRKCD variants and M1/M2 phenotype, as well as between a PKCδ KO-like gene signature and clinical benefit from anti-PD-1. Our results identify PKCδ as a candidate therapeutic target that modulates myeloid cell states.

TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids.

Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to resistance to CAR T-cell therapy in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. In this study, we examined the activity of B7-H3-directed CAR T cells (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS) and then confirmed the activity of B7-H3.CAR T cells in PDOTS. Although B7-H3 expression in PDOTS was associated with B7-H3.CAR-T sensitivity, mechanistic studies revealed dynamic upregulation of co-inhibitory receptors on CAR T-cells following target cell encounter that led to CAR T-cell dysfunction and limited efficacy against B7-H3-expressing tumors. PD-1 blockade restored CAR T-cell activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR T-cell efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR T-cell activity in monotypic and organotypic tumor spheroids, prevented CAR T-cell dysfunction, and enhanced CAR T-cell proliferation. Inhibition or deletion of TBK1 also enhanced the sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR T cells using PDOTS and suggest that targeting TBK1 could be used to enhance CAR T-cell efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms.

Landscape of transarterial chemoembolization represented interventional therapy for hepatocellular carcinoma.

This article discusses the article written by Tan et al. Transarterial chemoembolization (TACE) is one of the main treatment methods for advanced hepatocellular carcinoma (HCC). There are other vascular interventional therapies, including drug-eluting bead TACE, transarterial radioembolization, and hepatic arterial infusion chemotherapy. TACE combined with anti-angiogenesis therapy may improve tumor control and prolong progression free survival. The combination therapy of TACE and immunotherapy may improve the clinical efficacy of HCC. In future research, more basic and clinical studies are needed to explore the immunogenic intervention therapy.

Abstract A017: The FES tyrosine kinase as an emerging target for cancer immunotherapy

Abstract Immunotherapies are a promising emerging pillar of cancer treatment, but they still face many barriers due to the immunosuppressive nature of cancer. Cancer immunotherapy relies on the interplay between innate and adaptive immune responses. One way of stimulating such responses, known as immunogenic cell death (ICD), involves the release of tumour-associated antigens and damage associated molecular patterns (DAMPs). These DAMPs function to recruit and activate innate immune cells, including antigen-presenting cells (APCs), through engagement of pattern recognition receptors (PRRs), subsequently leading to production of the pro-inflammatory Signal 3 cytokines required for activation of adaptive immune cells (e.g., cytotoxic T lymphocytes [CTLs] and natural killer [NK] cells). The tyrosine kinase Fes suppresses innate immune responses in APCs by inhibiting components of the PRR signaling cascade. In non-cancer contexts, the negative regulation of APCs by Fes may guard against consequences of overactive innate immunity, including endotoxic shock or autoimmune disease. However, this same inhibitory effect on APC function may also serve as a checkpoint to successful anti-cancer immunotherapy, by obstructing efficient priming of cancer specific CTLs by APCs. Therefore, by inhibiting Fes, we hypothesize there will be greater Signal 3 cytokine production, resulting in greater CTL activation, and therefore improved tumor control. Using bone marrow derived APCs, including macrophages (BMDMs) and dendritic cells (BMDCs), from wildtype (WT) or Fes knockout (fes-/-) mice, we have shown through both Western blotting and flow cytometry analysis, that PRR signal transduction cascades are suppressed by Fes and increase levels of Signal 3 cytokines produced by fes-/- APCs. This includes higher levels of cell associated IL-12 in fes-/- APCs. Using syngeneic orthotopic mouse engraftment models of triple negative breast cancer (EO771) and melanoma (B16-F10) we showed that treatment with doxorubicin (which induces ICD) or anti-PD-1 (immune checkpoint inhibitor) plus doxorubicin controls tumor growth and prolongs survival to a greater extent in fes-/- mice. Immunophenotyping of tumors and spleens from these mice showed higher levels of activated CTLs and skewing of macrophages to a M1 state in fes-/- mice. SIINFEKL peptide loaded-BMDM/BMDCs from fes-/- mice were also more effective at priming CTLs from OT-1 mice (which express a T cell receptor that recognizes the SIINFEKL peptide) in antigen cross-presentation co-culture assays. These results implicate Fes as a potential novel immune checkpoint whose inhibition may enhance anti-cancer immunotherapy by suppressing its role in dampening inflammatory Signal 3 cytokine production by APCs. I will present recent data exploring the role of Fes in regulating the expression and trafficking of IL-12 in APCs to better understand the molecular basis of improved CTL activation by fes-/- APCs. Citation Format: Julian Simonetti, Brian J. Laight, Natasha Dmytryk, Danielle Harper, Yan Gao, Changnian Shi, Madhuri Koti, Sameh Basta, Peter A. Greer. The FES tyrosine kinase as an emerging target for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A017.

Clinical characteristics and outcome of central nervous system tumors harboring NTRK gene fusions.

TRK fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. We conducted an international retrospective cohort study of patients with TRK fusion-driven CNS tumors. 119 patients were identified. The median age at time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG) (57.1%) followed by low-grade glioma (LGG) (27.7%). Pediatric patients had a better prognosis with a median overall survival of 185.5 months compared to 24.8 months in adults (p<.0001). Patients with LGG also had a better outcome when compared to HGG (p=0.0012). The objective response was 68.8% with larotrectinib compared to 38.1% for non-targeted treatment. Children with LGG glioma had a favorable outcome compared to adult and HGG. TRK inhibitors appear to improve tumor control.

An engineered α1β1 integrin-mediated FcγRI signaling component to control enhanced CAR macrophage activation and phagocytosis

Treatment of solid tumors remains difficult, and therefore there has been increased focus on chimeric antigen receptor macrophages (CAR-M) to challenge solid tumors. However, CAR domain design of of adoptive cell therapy, which leads to differences in antitumor activity and triggered antitumor potential, remains poorly understood for macrophages. We developed an α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component for CAR-M specific activation and its antitumor potential. We evaluated CAR-M effects with α1β1 integrin-mediated FcγRI signaling (ACT CAR-M) on the activation and antitumor phagocytic response of macrophages in vitro. Subcutaneous tumor model in BALB/c mice and carcinomatosis model in immunodeficient mice were used to test the antitumor effect of ACT CAR-M compared with CD3ζ CAR-M. The α1β1 integrin-mediated FcγRI signaling engagement of CAR-M was associated with enhanced macrophage activation and specific phagocytosis in primary human macrophages, and significantly improved tumor control and survival in multiple cancer models when compared to CD3ζ CAR-M. RNA-sequencing suggested that α1β1 integrin-mediated FcγRI engagement increased antitumor immunity by enhancing pro-inflammatory M1 phenotype-associated pathways, such as Toll-like receptor signaling, tumor necrosis factor signaling, and IL-17 signaling. α1β1 integrin-mediated FcγRI signaling engagement markedly enhanced antitumor effects of CAR-M immunotherapy, which is proposed as an advanced engineering CAR domain material to expand the clinical application of CAR-M.

A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expression

The uniqueness in each person’s cancer cells and variation in immune infiltrates means that each tumor represents a unique problem, but therapeutic targets can be found among their shared features. Radiation therapy alters the interaction between the cancer cells and the stroma through release of innate adjuvants. The extranuclear DNA that can result from radiation damage of cells can result in production of the second messenger cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) by cyclic GMP-AMP synthase (cGAS). In turn, cGAMP can activate the innate sensor stimulator of interferon genes (STING), resulting in innate immune activation. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is a phosphodiesterase that can be expressed by cancer cells that can degrade cGAMP, thus can decrease or block STING activation following radiation therapy, impairing the innate immunity that is critical to support adaptive immune control of tumors. We observed that many human and murine cancer cells lack Enpp1 expression, but that Enpp1 is expressed in cells of the tumor stroma where it limits tumor control by radiation therapy. We demonstrate in preclinical models the efficacy of a novel Enpp1 inhibitor and show that this inhibitor improves tumor control by radiation even where the cancer cells lack Enpp1. This mechanism requires STING and type I interferon (IFN) receptor expression by non-cancer cells and is dependent on CD8 T cells as a final effector mechanism of tumor control. This suggests that Enpp1 inhibition may be an effective partner for radiation therapy regardless of whether cancer cells express Enpp1. This broadens the potential patient base for whom Enpp1 inhibitors can be applied to improve innate immune responses following radiation therapy.

Adenoviral-vectored neoantigen vaccine augments hyperexpanded CD8+ T cell control of tumor challenge in mice

BackgroundNeoantigens are promising immunogens for cancer vaccines and are often delivered as adjuvanted peptide vaccines. Adenoviral (Ad) vectors have been shown to induce strong CD8+ T cell responses as vaccines...

Carbon ion radiation therapy in prostate cancer: The importance of dosage.

In this article, we comment on the article by Ono et al. We focus specifically on the carbon ion radiotherapy studies and the method to calculate the dosing schedule. While photon hypofractionated radiotherapy in prostate cancer has demonstrated improvement in tumor control with reduced gastrointestinal toxicity compared to conventional radiotherapy, carbon ion radiotherapy (CIRT) offers additional physical and biological advantages. Recent findings, including those from Ono et al, have established new dose constraints of CIRT for prostate cancer treatment and risk factors for rectal bleeding. Due to limited data on CIRT dosing, this study underscores the need for more research to refine dose calculation methods and better understand their effects on clinical outcomes.

Outcome and toxicities of postmastectomy radiotherapy with integral cervicothoracic thermoplastic mask

BackgroundAppropriate immobilization setup for postmastectomy radiotherapy may help to improve tumor control and to reduce radiation-related toxicities. This study aims at retrospectively evaluate the outcome and toxicities of postmastectomy radiotherapy (PMRT) with a novel integral cervicothoracic thermoplastic mask strategy.MethodsBreast cancer patients were treated with modified radical mastectomy and PMRT. Patient immobilization setup was performed with the placement of a 1-cm thickened wax film on the ipsilateral chest wall and an integral cervicothoracic thermoplastic mask. PMRT was delivered according to the institutional protocol. Dose distribution, disease control, patient survival and radiation-induced toxicities were evaluated.ResultsFour-hundred nineteen eligible patients with complete follow-up information were included in the final analysis. The median follow-up was 40.2 (95%CI: 38.9–41.6) months. Two (0.5%) patients had local recurrence and 48 (11.4%) patients had distant metastasis. There were 22 (5.3%) deaths from all causes, of which 19 were caused by breast cancer. The 3-year overall survival (OS) rate was 94.8%. ER status, PR status, triple negative status, and T stages were significantly related to patient survival (p < 0.05). HER2 expression, N stage were not significantly related to patient survival. Most common radiation-induced toxicities included grade I (87.6%) and grade II (10.2%) dermatitis, and grade I pneumonitis (28.9%) found by chest X-ray or CT scans. No clinical detectable cardiovascular event related to radiotherapy was identified.ConclusionPostmastectomy radiotherapy with integral cervicothoracic thermoplastic mask leads to favorable outcome and moderate toxicities compared with results reported in literature and might be of clinical significance in breast cancer patient. However, this approach has not been compared directly with postmastectomy radiotherapy without immobilization, and its applicability in other regions with different treatment protocols requires further investigation.

H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response.

The role of tumor microenvironment (TME)-associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function is largely unknown. Here, we show that disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, was reverted upon treatment with hydrogen sulfide (H2S) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous H2S, which also promoted stemness, antioxidant capacity, and increased protein translation, mediated in part by endoplasmic reticulum-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous H2S or overexpressing CBS demonstrated superior tumor control upon adoptive transfer. Further, T cells with high Golgi content exhibited unique metabolic and glycation signatures with enhanced antitumor capacity. These data suggest that strategies to mitigate Golgi network stress or using Golgihi tumor-reactive T cells can improve tumor control upon adoptive transfer.

A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.

Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC. We describe a Tri-specific Killer Engager (TriKE) construct that engages with the activating receptor CD16 on NK cells, prostate-specific membrane antigen (PSMA) on mCRPC cells, and has an interleukin (IL)-15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation and cytokine production of NK cells derived from healthy donors or prostate cancer patients. Bystander killing of PSMA-negative was also achieved with PSMA TriKE treatment when co-cultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment (TME), NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or MDSCs maintained their potent function while IL-15 treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared to IL-15 and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their anti-tumor potential in prostate cancer, especially in the setting of a hostile TME.

Optimization Processes of Clinical Chelation-Based Radiopharmaceuticals for Pathway-Directed Targeted Radionuclide Therapy in Oncology.

Targeted radionuclide therapy (TRT) for internal pathway-directed treatment is a game changer for precision medicine. TRT improves tumor control while minimizing damage to healthy tissue and extends the survival for patients with cancer. The application of theranostic-paired TRT along with cellular phenotype and genotype correlative analysis has the potential for malignant disease management. Chelation chemistry is essential for the development of theranostic-paired radiopharmaceuticals for TRT. Among image-guided TRT, 68Ga and 99mTc are the current standards for diagnostic radionuclides, while 177Lu and 225Ac have shown great promise for β- and α-TRT, respectively. Their long half-lives, potent radiobiology, favorable decay schemes, and ability to form stable chelation conjugates make them ideal for both manufacturing and clinical use. The current challenges include optimizing radionuclide production processes, coordinating chelation chemistry stability of theranostic-paired isotopes to reduce free daughters [this pertains to 225Ac daughters 221Fr and 213Bi]-induced tissue toxicity, and improving the modeling of micro dosimetry to refine dose-response evaluation. The empirical approach to TRT delivery is based on standard radionuclide administered activity levels, although clinical trials have revealed inconsistent outcomes and normal-tissue toxicities despite equivalent administered activities. This review presents the latest optimization methods for chelation-based theranostic radiopharmaceuticals, advancements in micro-dosimetry, and SPECT/CT technologies for quantifying whole-body uptake and monitoring therapeutic response as well as cytogenetic correlative analyses.

TET2 regulates early and late transitions in exhausted CD8+ T cell differentiation and limits CAR T cell function.

CD8+ T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting TET2 in CAR T cells provides therapeutic benefit; however, TET2's role in exhausted T cell (TEX) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell-like TEX progenitors toward terminally differentiated and effector (TEFF)-like TEX. TET2 also enforced a terminally differentiated state in the early bifurcation between TEFF and TEX, indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable TET2-targeted CAR T cells by disrupting TET2 via knock-in of a safety switch alongside CAR knock-in at the TRAC locus. TET2-targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in TEX differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.