Injectable hydrogels for personalized cancer immunotherapies.

The field of cancer immunotherapy has shown significant growth, and researchers are now focusing on effective strategies to enhance and prolong local immunomodulation. Injectable hydrogels (IHs) have emerged as versatile platforms for encapsulating and controlling the release of small molecules and cells, drawing significant attention for their potential to enhance antitumor immune responses while inhibiting metastasis and recurrence. IHs delivering natural killer (NK) cells, T cells, and antigen-presenting cells (APCs) offer a viable method for treating cancer. Indeed, it can bypass the extracellular matrix and gradually release small molecules or cells into the tumor microenvironment, thereby boosting immune responses against cancer cells. This review provides an overview of the recent advancements in cancer immunotherapy using IHs for delivering NK cells, T cells, APCs, chemoimmunotherapy, radio-immunotherapy, and photothermal-immunotherapy. First, we introduce IHs as a delivery matrix, then summarize their applications for the local delivery of small molecules and immune cells to elicit robust anticancer immune responses. Additionally, we discuss recent progress in IHs systems used for local combination therapy, including chemoimmunotherapy, radio-immunotherapy, photothermal-immunotherapy, photodynamic-immunotherapy, and gene-immunotherapy. By comprehensively examining the utilization of IHs in cancer immunotherapy, this review aims to highlight the potential of IHs as effective carriers for immunotherapy delivery, facilitating the development of innovative strategies for cancer treatment. In addition, we demonstrate that using hydrogel-based platforms for the targeted delivery of immune cells, such as NK cells, T cells, and dendritic cells (DCs), has remarkable potential in cancer therapy. These innovative approaches have yielded substantial reductions in tumor growth, showcasing the ability of hydrogels to enhance the efficacy of immune-based treatments. STATEMENT OF SIGNIFICANCE: As cancer immunotherapy continues to expand, the mode of therapeutic agent delivery becomes increasingly critical. This review spotlights the forward-looking progress of IHs, emphasizing their potential to revolutionize localized immunotherapy delivery. By efficiently encapsulating and controlling the release of essential immune components such as T cells, NK cells, APCs, and various therapeutic agents, IHs offer a pioneering pathway to amplify immune reactions, moderate metastasis, and reduce recurrence. Their adaptability further shines when considering their role in emerging combination therapies, including chemoimmunotherapy, radio-immunotherapy, and photothermal-immunotherapy. Understanding IHs' significance in cancer therapy is essential, suggesting a shift in cancer treatment dynamics and heralding a novel period of focused, enduring, and powerful therapeutic strategies.

Activity of TNT: a phase 2 study using talimogene laherparepvec, nivolumab and trabectedin for previously treated patients with advanced sarcomas (NCT# 03886311).

Background: Intratumoral injection of talimogene laherparepvec evokes a cytotoxic immune response. Therefore, the combination of talimogene laherparepvec with trabectedin and nivolumab may have synergistic effects in advanced sarcomas. Patients and methods: This phase 2 trial was conducted from May 30, 2019 to January 31, 2022. Endpoints: Primary: Progression free survival rate at month 12. Secondary: Best overall response, progression free survival rate at 6 and 9 months, overall survival rate at 6, 9, and 12 months, incidence of conversion of an unresectable tumor to a resectable tumor, and incidence of adverse events. Eligible patients had to be ≥ 18 years of age, have advanced histologically proven sarcoma, at least 1 previous chemotherapy regimen, and at least one accessible tumor for intratumoral injection. Treatment: Trabectedin intravenously (1.2 mg/m2 q3 weeks), nivolumab intravenously (3 mg/kg q2 weeks), and intratumoral talimogene laherparepvec (1x108 plaque forming units/ml q2 weeks). Results: Median time of follow-up: 15.2 months. Efficacy analysis: Thirty-nine patients who had completed at least one treatment cycle and had a follow-up computerized tomography were evaluable for efficacy analysis. Median number of prior therapies: 4 (range 1-11). Progression free survival rate at month 12, 36.7%. Confirmed Best Overall Response by Response Evaluation Criteria in Solid Tumors v1.1 = 3 partial responses, 30 stable disease, 6 progressive disease. Best Overall Response Rate, 7.7%, Disease Control Rate, 84.6%; median progression free survival, 7.8 (95% Confidence Intervals: 4.1-13.1) months; 6-, 9-, 12-month progression free survival rates, 54.5%/45.9%/36.7%; median overall survival 19.3 (95% Confidence Intervals: 12.8 -.) months; 6-, 9- and 12-month overall survival rate, 86.9%/73.3%/73.3%. One patient had a complete surgical resection. Fifty percent of patients had a ≥ grade 3 treatment related adverse events which included anemia (6%), thrombocytopenia (6%), neutropenia (4%), increased alanine transaminase (4%), decreased left ventricular ejection fraction (4%), dehydration (4%), hyponatremia (4%). Conclusions: Taken together these data suggest that the TNT regimen is effective and safe for advanced previously treated sarcomas, and is worth being further studied in a randomized phase 3 trial as first- or second- line treatment for patients with advanced sarcomas.

Results of NC-6300 (Nanoparticle Epirubicin) in an Expansion Cohort of Patients with Angiosarcoma.

BACKGROUND: NC-6300 is a novel epirubicin (EPI) drug conjugated polymeric micelle developed using cutting-edge micellar nanoparticle technology. The nanoparticle epirubicin conjugates EPI to a polymer via a pH-sensitive linker which enables the selective EPI release into tumor. Tumor activity was observed in a monotherapy phase Ib trial, where two of two patients with angiosarcoma achieved a partial response. To further explore the activity of NC-6300 in angiosarcoma, an expansion cohort was undertaken. METHODS: Ten patients with angiosarcoma were enrolled in the expansion cohort. Patients were dosed using the recommended dose of 150 mg/m2 intravenously (IV) once every 3 weeks. The primary endpoint was progression-free survival. RESULTS: The most common adverse events (AEs) of any grade, regardless of the causal relationship with NC-6300, were neutropenia (90%), fatigue, and thrombocytopenia (60% each) and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). The median progression-free survival (mPFS) for all subjects was 5.4 months. The mPFS was 3.8 months in subjects with prior anthracycline treatment and 8.2 months in subjects without prior anthracycline treatment. CONCLUSION: NC-6300 was well tolerated, showing promising activity in angiosarcoma patients without prior anthracycline treatment. NC-6300 warrants further investigation (ClinicalTrials.gov Identifier: NCT03168061).

Evaluation of Crohn Disease Activity Using a Potential Abbreviated MRE Protocol Consisting of Balanced Steady-State Free Precession MRI Only Versus Full-Protocol MRE.

OBJECTIVE. The purpose of the present study was to compare the diagnostic performance of an abbreviated MR enterography (MRE) protocol consisting of balanced steady-state free-precession (b-SSFP) imaging only versus standard full-protocol MRE for the evaluation of Crohn disease activity. MATERIALS AND METHODS. This single-center retrospective study included 112 patients with Crohn disease (66 women and 46 men; age range, 18-84 years) who underwent MRE between January 2017 and March 2018. Utilizing binary and 5-point Likert confidence scales, two blinded readers independently interpreted and scored disease activity on b-SSFP sequences only and on full-protocol MRE images. Interreader and intrareader agreement on confidence regarding disease activity were calculated using weighted kappa indexes. Correlation between MRE findings of Crohn disease and the Harvey-Bradshaw index was also performed. RESULTS. Perfect intrareader agreement and strong interreader agreement on disease activity were observed (intrareader agreement: κ = 0.97, 0.96, and 0.96 for reader A, reader B, and both readers combined; interreader agreement: κ = 0.82 for b-SSFP imaging only and κ = 0.81 for MRE). For detecting active Crohn disease, b-SSFP sequences had a sensitivity and specificity of 97% and 100%, respectively, for reader A and 98% and 86%, respectively, for reader B. Strong-to-perfect intrareader agreement was achieved between b-SSFP imaging only and MRE for identification of penetrating disease (κ = 0.80 and 0.97) and stenosing disease (κ = 0.87 and 0.95). Perfect intrareader agreement was also obtained between b-SSFP imaging only and MRE for detecting abnormal bowel segments (κ = 0.91 for reader A; κ = 0.98 for reader B). Weak agreement was noted between both b-SSFP imaging only and MRE versus the Harvey-Bradshaw index (κ = 0.08 of reader A; κ = 0.04 for reader B). CONCLUSION. Robust agreement was observed between b-SSFP imaging only and full-protocol MRE for the assessment of Crohn disease activity and complications. An abbreviated MRE protocol that exclusively uses b-SSFP sequences appears feasible and has significant implications for health care resources.

Intralesional Injection of Bone Marrow Aspirate Concentrate for the Treatment of Osteonecrosis of the Knee Secondary to Systemic Lupus Erythematosus: A Case Report.

Case: An 18-year-old female patient with Systemic Lupus Erythematosus (SLE) and corticosteroid-associated extensive bilateral symptomatic knee Osteonecrosis (ON) (Ficat IV), treated with sequential intralesional injections of autologous bone marrow aspirate concentrate (BMAC) under ultrasound guidance. At 3 months, pain was almost absent (VAS) and KOOS/WOMAC showed significant improvement sustained up to 24 months. At 12 months MRI indicated bone maturation, significantly reduced BM edema and subchondral fluid volume, and no collapse/fragmentation signs. Discussion: The clinical and imaging significant improvement observed in this patient suggests that BMAC intralesional injections effectively restored the compromised bone structure. After larger studies, this technique can become an alternative to decompressing surgery for ON cases.

An automated two-phase system for hydrogel microbead production.

Polymeric beads have been used for protection and delivery of bioactive materials, such as drugs and cells, for different biomedical applications. Here, we present a generic two-phase system for the production of polymeric microbeads of gellan gum or alginate, based on a combination of in situ polymerization and phase separation. Polymer droplets, dispensed using a syringe pump, formed polymeric microbeads while passing through a hydrophobic phase. These were then crosslinked, and thus stabilized, in a hydrophilic phase as they crossed through the hydrophobic-hydrophilic interface. The system can be adapted to different applications by replacing the bioactive material and the hydrophobic and/or the hydrophilic phases. The size of the microbeads was dependent on the system parameters, such as needle size and solution flow rate. The size and morphology of the microbeads produced by the proposed system were uniform, when parameters were kept constant. This system was successfully used for generating polymeric microbeads with encapsulated fluorescent beads, cell suspensions and cell aggregates proving its ability for generating bioactive carriers that can potentially be used for drug delivery and cell therapy.