scholarly journals Sarcoma Immunotherapy: Past Approaches and Future Directions

Sarcoma ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
S. P. D'Angelo ◽  
W. D. Tap ◽  
G. K. Schwartz ◽  
R. D. Carvajal
Keyword(s):  
Malignant Tumors ◽  
Therapeutic Option ◽  
Interleukin 2 ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Antigen Receptors ◽  
Curative Intent ◽  
Future Directions ◽  
Metastatic Setting ◽  
Made In

Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease.

Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1399-1403 ◽  
Author(s):  
Gullu Gorgun ◽  
Francine Foss
Keyword(s):  
T Cell ◽  
B Cell ◽  
Retinoic Acid Receptor ◽  
Interleukin 2 ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Immunomodulatory Effects ◽  
Denileukin Diftitox ◽  
High Affinity ◽  
T Cell Lymphomas

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10−6 to 10−10 M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R–targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.

scholarly journals The Efficacy of Combined Cisplatin and Nanoparticle Albumin-Bound Paclitaxel in a Stage IV Pancreatic Squamous Cell Carcinoma Patient With a Somatic BRCA2 Mutation: A Case Report

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaozhun Huang ◽  
Chunling Wang ◽  
Teng Ma ◽  
Zhangkan Huang ◽  
Houhong Zhou ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Therapeutic Option ◽  
Brca2 Mutation ◽  
Stage Iv ◽  
Clinical Activity ◽  
R0 Resection ◽  
Metastatic Setting ◽  
Radical Antegrade Modular Pancreatosplenectomy

Pancreatic squamous cell carcinoma (SCC) is a rare primary pancreatic malignancy with a poor prognosis. The median overall survival (OS) for metastatic setting is only 4 months and the optimal management remains poorly defined. In the present study, we report a 52-year-old female patient with stage IV primary SCC of the pancreas harboring a deleteous BRCA2 somatic mutation. After 10 cycles of chemotherapy of cisplatin combined with nanoparticle albumin-bound paclitaxel, metastatic lesions in the liver and lymph nodes achieved radiographic complete responses and pancreatic lesion shrank from 5.7 to 1.5 cm in diameter. The patient subsequently underwent a posterior radical antegrade modular pancreatosplenectomy with R0 resection and residual liver lesions were also resected. After 3 months, a tumor relapsed in the liver. She was then treated with olaparib combined with pembrolizumab and achieved stable disease on the liver lesion. The patient eventually died from cerebral hemorrhage with a long OS of 21 months. Our case demonstrated a favorable clinical activity and survival advantage of the combined cisplatin and nanoparticle albumin-bound paclitaxel, which might serve as a therapeutic option for the patient with BRCA-mutant pancreatic SCC.

Clinical activity and safety of simlukafusp alfa, an engineered interleukin-2 variant targeted to fibroblast activation protein-α, combined with atezolizumab in patients with recurrent or metastatic cervical cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5510-5510
Author(s):  
Antoine Italiano ◽  
Loic Verlingue ◽  
Hans Prenen ◽  
Eva M. Guerra ◽  
Diego Tosi ◽  
...  
Keyword(s):  
Objective Response ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
Complete Response ◽  
Cervical Squamous Cell Carcinoma ◽  
Median Number ◽  
Fibroblast Activation Protein ◽  
Clinical Activity ◽  
Fibroblast Activation ◽  
Metastatic Setting

5510 Background: Simlukafusp alfa (SIM; FAP-IL2v) comprises an interleukin-2 variant (IL-2v) moiety and an antibody against fibroblast activation protein-α (FAP). The binding of SIM to FAP, expressed on cancer-associated fibroblasts, accounts for retention and accumulation in malignant lesions. The engineered IL-2v moiety has an abolished binding to IL-2Rα while the affinity to IL-2Rβγ is retained, resulting in activation of immune effector CD8 T and NK cells, but not of regulatory T cells, and therefore may augment activity of PD-(L)1 inhibitors. Methods: The clinical activity and safety of the SIM and atezolizumab (ATZ) combination in patients with recurrent or metastatic (R/M) cervical squamous cell carcinoma (SCC) were evaluated in a phase 2 basket study (NCT03386721). Patients (pts) were treated with SIM 10 mg IV and ATZ 1200 mg IV once every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1 assessed by investigators. Secondary endpoints were: disease control rate (DCR), duration of response (DoR), progression free survival (PFS). Results: 47 Pts with ECOG ≥1 and median age of 53 years (range: 25-69) were enrolled. All pts were checkpoint inhibitor naïve and 40 (85%) had ≥ 1 previous lines of therapy in the metastatic setting. The median number of cycles was 6 (range: 1-29). The ORR was 27% (90% CI: 18, 39) and DCR was 71% (90% CI: 58, 80) in 44 response-evaluable patients: 2 (5%) had complete response, 10 (23%) partial response, and 19 (43%) stable disease. Responses were observed across PD-L1 subgroups (SP142 assay, IC/TC cut-off ≥ 1%) with 8/22 and 4/18 responders in PD-L1+ and PD-L1- patients, respectively. Responses were durable, the median DoR was 13.3 months (95% CI: 7.6, 14.7). PFS probability at 6 months was 0.4 (95% CI: 0.27, 0.59). The most common adverse events (AE) (reported in > 30% patients), irrespective of relatedness to treatment and severity, were pyrexia (74.5%), anemia (48.9%), asthenia (48.9%), AST increased (44.7%), nausea (42.6%), ALT increased (42.6%), vomiting (36.2%) and diarrhea (31.9%). Grade 3 and 4 AEs related to SIM were observed in 63.8 % and 29.8 % of pts, respectively, while serious AEs (SAE) related to SIM were reported in 40.4%. The most common SAEs (reported in > 5% pts) irrespective of relatedness to treatment were infusion related reaction (14.9%), pyrexia (6.4%) and hydronephrosis (6.4%). One Grade 5 event occurred, which was unrelated to treatment. Conclusions: SIM in combination with ATZ demonstrated an acceptable safety profile in pts with R/M cervical SCC. The anti-tumor activity compares favorably to the approved PD-1 inhibitors in this setting and supports further exploration of IL-2v and checkpoint inhibition in this patient population of high unmet medical need. Clinical trial information: NCT03386721.

The potentiality of immunotherapy for sarcomas: a summary of potential predictive biomarkers

2020 ◽  
Vol 16 (17) ◽  
pp. 1211-1223 ◽  
Author(s):  
Jin Liang ◽  
Dedian Chen ◽  
Liyao Chen ◽  
Xueke She ◽  
Hushan Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Side Effects ◽  
Malignant Tumors ◽  
Immune Surveillance ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Small Cell Lung ◽  
Curative Intent ◽  
Metastatic Setting ◽  
Potential Biomarkers

Sarcomas are rare and heterogeneous malignant tumors of mesenchymal origin. A total of 25–50% of patients treated with initial curative intent will develop as recurrent and metastatic disease. In the recurrent and metastatic setting, effect of chemotherapy is limited; therefore, more effective therapies are urgently desired. As a brake for activation of T cell, PD-1/PD-L1 plays a crucial role in the progression of tumor by altering status of immune surveillance. Some success has been acquired recently in the use of PD-1/PD-L1 inhibitors for the treatment of several solid tumors, for examples, non-small-cell lung cancer and melanoma. Immunotherapeutic strategies based on PD-1/PD-L1 for sarcomas have also been explored these years. As in other cancers, major challenges are identification of biomarkers to predict response for immunotherapy, optimization of patient’s benefit and minimization of side effects. Therefore, we focused on potential biomarkers of immunotherapy for treatment of sarcomas in this review.

Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous T-cell lymphoma.

1993 ◽  
Vol 11 (9) ◽  
pp. 1682-1690 ◽  
Author(s):  
P Hesketh ◽  
P Caguioa ◽  
H Koh ◽  
H Dewey ◽  
A Facada ◽  
...  
Keyword(s):  
T Cell ◽  
Fusion Protein ◽  
Interleukin 2 ◽  
Common Adverse Effect ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
T Cell Lymphomas ◽  
Hepatic Transaminases ◽  
Heavily Pretreated ◽  
Pretreated Patients

PURPOSE A phase I trial in patients with refractory hematologic malignancies was performed at our institution to test the clinical relevance of the selective cytotoxic activity of the interleukin-2 (IL-2)-diphtheria toxin fusion protein, DAB486IL-2. A subset of five patients from this trial, all with cutaneous T-cell lymphomas (CTCL), forms the basis of this report. PATIENTS AND METHODS Two treatment schedules were used. One patient received DAB486IL-2 at a dose of 0.075 mg/kg/d intravenous (i.v.) bolus over 15 minutes daily for 5 consecutive days. The other four patients received DAB486IL-2 at a dose of 0.1 mg/kg as an i.v. infusion over 180 minutes weekly for 5 consecutive weeks. RESULTS Three of the five CTCL patients achieved significant tumor responses. One patient attained a complete clinical and pathologic response (CR), which has been sustained without any interval treatment for 33+ months. Two other patients achieved partial responses (PRs) of 17+ and 4 months' duration, respectively. Treatment was well tolerated. The most common adverse effect was a transient increase in hepatic transaminases experienced by all five patients. CONCLUSION The growth factor-cytotoxin fusion protein DAB486IL-2 demonstrated significant clinical activity with acceptable toxicity in a group of heavily pretreated patients with CTCL.

The new in monitoring of provision of cancer care in the Russian Federation

2019 ◽  
Vol 2019 (4) ◽  
pp. 35-37
Author(s):  
Наталья Стадченко ◽  
Natal'ya Stadchenko
Keyword(s):  
Russian Federation ◽  
Treatment Guidelines ◽  
Malignant Tumors ◽  
Patient Specific ◽  
Insurance Fund ◽  
Medical Aid ◽  
Proven Case ◽  
The Russian Federation ◽  
Positive Results ◽  
Made In

The Federal Compulsory Medical Insurance Fund created the system of a monitoring of medical aid provided for the oncology patients, which allows realizing control over execution of the treatment guidelines on every stage. Changes been made in the governing documents, aimed at development of patient-specific records of provided medical aid at suspicion on the malignant tumors or in proven case of the malignant tumors. The article presents the data on control and expert activities demonstrating positive results of that work.

Inflammatory Markers Associated With Diabetes Mellitus – Old and New Players

2020 ◽  
Vol 26 ◽  
Author(s):  
Emir Muzurović ◽  
Zoja Stanković ◽  
Zlata Kovačević ◽  
Benida Šahmanović Škrijelj ◽  
Dimitri P Mikhailidis
Keyword(s):  
Diabetes Mellitus ◽  
Inflammatory Markers ◽  
High Specificity ◽  
Future Directions ◽  
Effective Strategies ◽  
Advantages And Disadvantages ◽  
Type 2 Dm ◽  
Increased Risk ◽  
Made In

: Diabetes mellitus (DM) is a chronic and complex metabolic disorder, and also an important cause of cardiovascular (CV) diseases (CVDs). Subclinical inflammation, observed in patients with type 2 DM (T2DM), cannot be considered the sole or primary cause of T2DM in the absence of classical risk factors, but it represents an important mechanism that serves as a bridge between primary causes of T2DM and its manifestation. Progress has been made in the identification of effective strategies to prevent or delay the onset of T2DM. It is important to identify those at increased risk for DM by using specific biomarkers. Inflammatory markers correlate with insulin resistance (IR) and glycoregulation in patients with DM. Also, several inflammatory markers have been shown to be useful in assessing the risk of developing DM and its complications. However, the intertwining of pathophysiological processes and the not-quite-specificity of inflammatory markers for certain clinical entities limits their practical use. In this review we consider the advantages and disadvantages of various inflammatory biomarkers of DM that have been investigated to date as well as possible future directions. Key features of such biomarkers should be high specificity, non-invasiveness and cost-effectiveness.

A Review of Evaluating Hematopoietic Stem Cells Derived from Umbilical Cord Blood's Expansion and Homing

2020 ◽  
Vol 15 (3) ◽  
pp. 250-262
Author(s):  
Maryam Islami ◽  
Fatemeh Soleimanifar
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Umbilical Cord ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Hematologic Malignancies ◽  
Future Directions ◽  
Hematopoietic Stem ◽  
Efficient Procedure ◽  
Hematopoietic Recovery

Transplantation of hematopoietic stem cells (HSCs) derived from umbilical cord blood (UCB) has been taken into account as a therapeutic approach in patients with hematologic malignancies. Unfortunately, there are limitations concerning HSC transplantation (HSCT), including (a) low contents of UCB-HSCs in a single unit of UCB and (b) defects in UCB-HSC homing to their niche. Therefore, delays are observed in hematopoietic and immunologic recovery and homing. Among numerous strategies proposed, ex vivo expansion of UCB-HSCs to enhance UCB-HSC dose without any differentiation into mature cells is known as an efficient procedure that is able to alter clinical treatments through adjusting transplantation-related results and making them available. Accordingly, culture type, cytokine combinations, O2 level, co-culture with mesenchymal stromal cells (MSCs), as well as gene manipulation of UCB-HSCs can have effects on their expansion and growth. Besides, defects in homing can be resolved by exposing UCB-HSCs to compounds aimed at improving homing. Fucosylation of HSCs before expansion, CXCR4-SDF-1 axis partnership and homing gene involvement are among strategies that all depend on efficiency, reasonable costs, and confirmation of clinical trials. In general, the present study reviewed factors improving the expansion and homing of UCB-HSCs aimed at advancing hematopoietic recovery and expansion in clinical applications and future directions.

scholarly journals Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wenhui Wang ◽  
Pengyu Liu ◽  
Marla Lavrijsen ◽  
Shan Li ◽  
Ruyi Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Target Genes ◽  
Therapeutic Option ◽  
Carcinoma Cell Lines ◽  
Hepatocellular Carcinomas ◽  
Enhanced Expression ◽  
Mutant Lines ◽  
Substantial Interest ◽  
Support Tumor Growth ◽  
Made In

AbstractAXIN1 mutations are observed in 8–10% of hepatocellular carcinomas (HCCs) and originally were considered to support tumor growth by aberrantly enhancing β-catenin signaling. This view has however been challenged by reports showing neither a clear nuclear β-catenin accumulation nor clearly enhanced expression of β-catenin target genes. Here, using nine HCC lines, we show that AXIN1 mutation or siRNA mediated knockdown contributes to enhanced β-catenin signaling in all AXIN1-mutant and non-mutant lines, also confirmed by reduced signaling in AXIN1-repaired SNU449 cells. Both AXIN1 and AXIN2 work synergistically to control β-catenin signaling. While in the AXIN1-mutant lines, AXIN2 is solely responsible for keeping signaling in check, in the non-mutant lines both AXIN proteins contribute to β-catenin regulation to varying levels. The AXIN proteins have gained substantial interest in cancer research for a second reason. Their activity in the β-catenin destruction complex can be increased by tankyrase inhibitors, which thus may serve as a therapeutic option to reduce the growth of β-catenin-dependent cancers. At concentrations that inhibit tankyrase activity, some lines (e.g. HepG2, SNU398) were clearly affected in colony formation, but in most cases apparently independent from effects on β-catenin signaling. Overall, our analyses show that AXIN1 inactivation leads to enhanced β-catenin signaling in HCC cell lines, questioning the strong statements that have been made in this regard. Enhancing AXIN activity by tankyrase monotherapy provides however no effective treatment to affect their growth exclusively through reducing β-catenin signaling.

scholarly journals Will mesenchymal stem cells be future directions for treating radiation-induced skin injury?

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhuoqun Fang ◽  
Penghong Chen ◽  
Shijie Tang ◽  
Aizhen Chen ◽  
Chaoyu Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Malignant Tumors ◽  
Skin Injury ◽  
Future Directions ◽  
Cytokines And Chemokines ◽  
Radiation Induced ◽  
The Common ◽  
Apoptotic Activity ◽  
Different Sources

AbstractRadiation-induced skin injury (RISI) is one of the common serious side effects of radiotherapy (RT) for patients with malignant tumors. Mesenchymal stem cells (MSCs) are applied to RISI repair in some clinical cases series except some traditional options. Though direct replacement of damaged cells may be achieved through differentiation capacity of MSCs, more recent data indicate that various cytokines and chemokines secreted by MSCs are involved in synergetic therapy of RISI by anti-inflammatory, immunomodulation, antioxidant, revascularization, and anti-apoptotic activity. In this paper, we not only discussed different sources of MSCs on the treatment of RISI both in preclinical studies and clinical trials, but also summarized the applications and mechanisms of MSCs in other related regenerative fields.

Sign in / Sign up

Export Citation Format

Share Document