Targeted chemotherapy via HER2-based chimeric antigen receptor (CAR) engineered T-cell membrane coated polymeric nanoparticles.

Cell membrane-derived nanoparticles (NPs) have recently gained popularity due to their desirable features in drug delivery such as mimicking properties of native cells, impeding systemic clearance, and altering foreign body responses. Besides NP technology, adoptive immunotherapy has emerged due to its promise in cancer specificity and therapeutic efficacy. In this research, we developed a biomimetic drug carrier based on chimeric antigen receptor (CAR) transduced T-cell membranes.

Radiation-Induced Innate Neutrophil Response in Tumor Is Mediated by the CXCLs/CXCR2 Axis.

The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is an early innate inflammatory response that occurs within 24-48 h. Using two different syngeneic murine tumor models (RM-9 and MC-38), we demonstrated that CXCR2 blockade significantly reduced RT-induced neutrophilic infiltration.

Systemic immune parameters after prior radiation therapy in patients receiving immune checkpoint inhibitors.

Introduction: Preclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI.

Phase 2 Trial of Stereotactic Ablative Radiotherapy for Patients with Primary Renal Cancer.

Background: Most renal cell carcinomas (RCCs) are localized and managed by active surveillance, surgery, or minimally invasive techniques. Stereotactic ablative radiation (SAbR) may provide an innovative non-invasive alternative although prospective data are limited.

Objective: To investigate whether SAbR is effective in the management of primary RCCs.

Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation for Patients with Metastatic Castrate-Resistant Prostate Cancer.

(1) We hypothesized that adding concurrent stereotactic ablative radiotherapy (SAbR) would increase the time to progression in patients with metastatic castrate-resistant prostate cancer (mCRPCA) treated with sipuleucel-T. (2) Patients with a history of prostate cancer (PC), radiographic evidence of metastatic disease, and rising prostate-specific antigen (PSA) > 0.2 ng/dL on castrate testosterone levels were enrolled in this single-arm phase II clinical trial and treated with sipuleucel-T and SAbR.

Renal Lipid Metabolism Abnormalities in Obesity and Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma is the most common and deadly type of cancer affecting the kidney, and is characterized histologically by large intracellular lipid deposits. These deposits are thought to result from lipid metabolic reprogramming occurring in tumor cells, but the exact mechanisms and implications of these metabolic alterations are incompletely understood. Obesity is an independent risk factor for clear cell renal cell carcinoma, and is also associated with lipid accumulation in noncancerous epithelial cells of the proximal tubule, where clear cell renal cell carcinoma originates.

Outcome and Immune Correlates of a Phase II Trial of High-Dose Interleukin-2 and Stereotactic Ablative Radiotherapy for Metastatic Renal Cell Carcinoma.

Purpose: This phase II clinical trial evaluated whether the addition of stereotactic ablative radiotherapy (SAbR), which may promote tumor antigen presentation, improves the overall response rate (ORR) to high-dose IL2 (HD IL2) in metastatic renal cell carcinoma (mRCC).

Patients And Methods: Patients with pathologic evidence of clear cell renal cell carcinoma (RCC) and radiographic evidence of metastasis were enrolled in this single-arm trial and were treated with SAbR, followed by HD IL2. ORR was assessed based on nonirradiated metastases.

Transcriptomic analysis links hepatocellular carcinoma (HCC) in HZE ion irradiated mice to a human HCC subtype with favorable outcomes.

High-charge, high-energy ion particle (HZE) radiations are extraterrestrial in origin and characterized by high linear energy transfer (high-LET), which causes more severe cell damage than low-LET radiations like γ-rays or photons. High-LET radiation poses potential cancer risks for astronauts on deep space missions, but the studies of its carcinogenic effects have relied heavily on animal models. It remains uncertain whether such data are applicable to human disease.

Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) in Preclinical Models Enhances Single-Agent Immune Checkpoint Blockade.

Purpose: Harnessing the immune-stimulatory effects of radiation by combining it with immunotherapy is a promising new treatment strategy. However, more studies characterizing immunotherapy and radiation dose scheduling for the optimal therapeutic effect is essential for designing clinical trials.

Methods And Materials: A new ablative radiation dosing scheme, personalized ultrafractionated stereotactic adaptive radiation therapy (PULSAR), was tested in combination with α-PD-L1 therapy in immune-activated and resistant syngeneic immunocompetent mouse models of cancer.

Neoadjuvant SABR for Renal Cell Carcinoma Inferior Vena Cava Tumor Thrombus-Safety Lead-in Results of a Phase 2 Trial.

Purpose: To evaluate the feasibility, safety, oncologic outcomes, and immune effect of neoadjuvant stereotactic radiation (Neo-SAbR) followed by radical nephrectomy and thrombectomy (RN-IVCT).

Methods And Materials: These are results from the safety lead-in portion of a single-arm phase 1 and 2 trial. Patients with kidney cancer (renal cell carcinoma [RCC]) and inferior vena cava (IVC) tumor thrombus (TT) underwent Neo-SAbR (40 Gy in 5 fractions) to the IVC-TT followed by open RN-IVCT.

Renal lipid accumulation, oxidative stress and uric acid handling in a rodent model of obesity and metabolic syndrome.

Hyperuricemia is more prevalent among people with obesity and metabolic syndrome, and is associated with adverse clinical outcomes. We hypothesized that increased renal reabsorption of uric acid (UA) in obesity and metabolic syndrome may be an adaptive response of the kidney when faced with fatty acid-induced oxidative stress. To test this hypothesis, we examined lipid accumulation, markers of oxidative stress, and renal UA handling in Zucker diabetic fatty (ZDF) rats, and in matched lean control animals.

Type I Interferon Response in Radiation-Induced Anti-Tumor Immunity.

The anti-tumor activity of interferons (IFNs) was first appreciated about half a century ago, and IFN-α2 was the first cancer immunotherapy approved by the US Food and Drug Administration. Radiation therapy (RT), one of the pillars of cancer treatment, directly causes DNA damage, which can lead to senescence and cell death in tumor cells. In recent years, however, RT-induced immunomodulatory effects have been recognized to play an indispensable role in achieving the optimum therapeutic effect of RT.

Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes.

Lack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy. Tumor neoantigens are critical targets of the host antitumor immune response, and their presence correlates with the efficacy of immunotherapy treatment. Many studies involving assessment of tumor neoantigens principally focus on total neoantigen load, which simplistically treats all neoantigens equally.

A randomized trial comparing the efficacy and safety of treating patients with type 2 diabetes and highly elevated HbA1c levels with basal-bolus insulin or a glucagon-like peptide-1 receptor agonist plus basal insulin: The SIMPLE study.

Aim: To compare the efficacy and safety of a glucagon-like peptide-1 receptor agonist (GLP1RA) plus basal insulin versus basal-bolus insulin treatment in patients with very uncontrolled type 2 diabetes.

Materials And Methods: The SIMPLE study was a 6-month pragmatic, randomized, open-label trial testing the effectiveness of two approaches to treat patients with type 2 diabetes and HbA1c ≥10%. We randomized patients to detemir plus liraglutide or detemir plus aspart (before each meal).

Roux-en-Y gastric bypass compared with equivalent diet restriction: Mechanistic insights into diabetes remission.

Aims: To investigate the physiological mechanisms leading to rapid improvement in diabetes after Roux-en-Y gastric bypass (RYGB) and specifically the contribution of the concurrent peri-operative dietary restrictions, which may also alter glucose metabolism.

Materials And Methods: In order to assess the differential contributions of diet and surgery to the mechanisms leading to the rapid improvement in diabetes after RYGB we enrolled 10 patients with type 2 diabetes scheduled to undergo RYGB. All patients underwent a 10-day inpatient supervised dietary intervention equivalent to the peri-operative diet (diet-only period), followed by, after a re-equilibration (washout) period, an identical period of pair-matched diet in conjunction with RYGB (diet and RYGB period).

The Infamous, Famous Sulfonylureas and Cardiovascular Safety: Much Ado About Nothing?

Purpose Of Review: Sulfonylureas (SUs) are one of the most commonly used glucose-lowering agents worldwide. While their efficacy is undisputed, their cardiovascular safety has been debated since the 1970's.

Recent Findings: With no dedicated cardiovascular studies to definitively answer this question, observational studies and meta-analyses abound and have reported divergent results, fueling the controversy.

The Role of Regulatory B Cell-Like Malignant Cells and Treg Cells in the Mouse Model of BCL1 Tumor Dormancy.

Cancer dormancy is a clinical state in which residual tumor cells persist for long periods of time but do not cause detectable disease. In the mouse B cell lymphoma model (BCL1), dormancy can be induced and maintained by immunizing mice with a soluble form of the IgM expressed on the surface of the tumor cells. Immunization induces an anti-idiotype antibody response that maintains dormancy.

Rationale and evidence to combine radiation therapy and immunotherapy for cancer treatment.

Cancer immunotherapy exploits the immune system's ability to differentiate between tumor target cells and host cells. Except for limited success against a few tumor types, most immunotherapies have not achieved the desired clinical efficacy until recently. The field of cancer immunotherapy has flourished with a variety of new agents for clinical use, and remarkable progress has been made in the design of effective immunotherapeutic regimens.

Key role for neutrophils in radiation-induced antitumor immune responses: Potentiation with G-CSF.

Radiation therapy (RT), a major modality for treating localized tumors, can induce tumor regression outside the radiation field through an abscopal effect that is thought to involve the immune system. Our studies were designed to understand the early immunological effects of RT in the tumor microenvironment using several syngeneic mouse tumor models. We observed that RT induced sterile inflammation with a rapid and transient infiltration of CD11bGr-1 neutrophils into the tumors.

The Immunogenicity of Peptoid-Protein Conjugates.

We demonstrate that a peptoid composed of five monomers and attached a maleimide linker to a carrier protein elicits anti-peptoid, anti-linker and anti-carrier antibodies in rabbits. Specific anti-peptoid antibodies were affinity purified and used to reproducibly retrieve three specific peptoid-coupled beads from 20,000 irrelevant peptoid-beads using magnetic screening.

Mechanisms of Action of Liraglutide in Patients With Type 2 Diabetes Treated With High-Dose Insulin.

Context: The mechanisms of action of incretin mimetics in patients with long-standing type 2 diabetes (T2D) and high insulin requirements have not been studied.

Objective: To evaluate changes in β-cell function, glucagon secretion, and fat distribution after addition of liraglutide to high-dose insulin.

Design: A single-center, randomized, double-blind, placebo-controlled trial.

A reevaluation of CD22 expression in human lung cancer.

CD22 is a transmembrane glycoprotein expressed by mature B cells. It inhibits signal transduction by the B-cell receptor and its coreceptor CD19. Recent reports indicate that most human lung cancer cells and cell lines express CD22, making it an important new therapeutic target for lung cancer.

Pancreatic ductal adenocarcinoma: a review of immunologic aspects.

With the continued failures of both early diagnosis and treatment options for pancreatic cancer, it is now time to comprehensively evaluate the role of the immune system on the development and progression of pancreatic cancer. It is important to develop strategies that harness the molecules and cells of the immune system to treat this disease. This review will focus primarily on the role of immune cells in the development and progression of pancreatic ductal adenocarcinoma and to evaluate what is known about the interaction of immune cells with the tumor microenvironment and their role in tumor growth and metastasis.

Immunotoxins constructed with chimeric, short-lived anti-CD22 monoclonal antibodies induce less vascular leak without loss of cytotoxicity.

An immunotoxin (IT) constructed with RFB4, a murine anti-CD22 monoclonal antibody, and the "deglycosylated" A chain of ricin has shown activity at safe doses in patients with non-Hodgkin lymphoma and in children with acute lymphoblastic leukemia. The dose limiting toxicity is vascular leak syndrome (VLS), which appears to be due to a unique amino acid motif in the ricin toxin A (RTA) chain that damages vascular endothelial cells. We mutated recombinant (r) RTA to disable this site, but await testing of the IT prepared with this mutant RTA in humans.