B cell receptor targeting and cancer therapy

B cell receptor targeting and cancer therapy

B cell receptor is involved in the normal B cell development and immunity but also in supporting the growth and survival of malignant B cells in patients with B cell leukaemias or lymphomas. The expression of this receptor on the surface of the B cells is important for the immune response. It triggers antigen-antibody responses and B cells differentiation into plasma sells and membrane B cells.

B cells activation is mediated by activation of membrane-proximal kinases like spleen tyrosine kinase (STK), Bruton tyrosine kinase (BTK) and PI3K. In the recent years there are inhibitors which are developed to target these kinases as part of the treatment of leukaemias and lymphomas. For example, some of the approved inhibitors are: Ibrutinib (BTK inhibitor) and Idelalisib (PI3K inhibitor). However, these inhibitors are not specific to tumour cells only and they can influence other processes in the healthy cells. Currently there are in development more specific inhibitors.

The treatment responses to these inhibitors can vary depending on the B cell receptor signalling and its interaction with the microenvironment. Also the genetic background and the degree of genetic instability could activate mechanisms which could lead to resistance to these drugs.

The role of B cells in solid tumours is not established yet but B cells are discovered in solid cancers like breast, cervical, ovarian, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. Tumour-infiltrated B cells and macrophages both express BTK and are targeted by BTK inhibitors.

While the kinases involved in B cell receptor activation are promising target more research is needed to develop specific inhibitors that will target cancer cells.

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Targeting B cell receptor signalling in cancer: preclinical and clinical advances

Published on 3 Sep 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

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DNA nanorobots and cancer treatment

DNA nanorobots and cancer treatment

A research team from National Center for Nanoscience and Technology, Beijing, China has reported an interesting and novel approach in targeting tumours. They have constructed autonomous DNA robots which were programmed to transport and deliver therapeutics directly to the tumours.

According to the research paper such DNA robots have already been studied in cell cultures and insects but not in animals.

One of the potential new methods to target solid tumours is vascular occlusion, which is a process of blocking the blood vessels (in this case the once that support tumour growth and spreading). The research team has decided to use this method and to target tumour cells with thrombin. Thrombin cannot exist for a long time on its own in the blood circulation and it is not specific when triggering coagulation processes.

The experiments were done with mouse models and Bama miniature pigs. They have picked Bama miniature pigs because their physiology is closer to humans. Also they have run experiments with different types of tumours with different level of vascularization. The final results have shown that the DNA nanorobots have successfully delivered thrombin to the tumours and have blocked the blood supplies to them without affecting surrounding cells.

According to the authors this is an important step forward in developing method which will allow targeting tumours and blocking formation of metastasis.

It is definitely a very promising field with great potential.

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A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo

Published on 1 August 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

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FDA legislation changes and clinical trials: July 2018

FDA legislation changes and clinical trials: July 2018

FDA extends access to experimental drugs

FDA extended access program started back in 2009 and it allowed patients with life-threatening diseases who have exhausted all other options to try experimental drugs, which are not on the market yet. After the implementation the program for the period between 2009 and 2014 FDA has approved almost 6000 requests for experimental treatment, however some view the current process as ineffective.

The new legislation ‘Federal Right to Try Act’ will further increase the access to experimental drugs and change the pathway to obtain approvals. However, the agency remains committed to protect patients’ safety and provide more treatment options to patients with life-threatening diseases.

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FDA prepares guidance on including adolescent in adult oncology clinical trials

It is known that cancer in young paediatric patients may differ from adults and therefor needs new approaches and treatments; there is an acute demand for treatment options for paediatric cancer patients. It was established that in some type of cancers there is similarity in paediatric and adult cancer histology and biological behaviour – for example, some soft tissue and bone sarcomas, central nervous system tumours, leukaemia, lymphomas and melanomas.

Often paediatric clinical trials are conducted long after adult trials and this could lead to delay in access to potentially effective therapies.

In June 2018 FDA released guidance on inclusion of adolescents (age between 12 and 17 years) in clinical trials. The guideline outlines appropriate criteria for inclusion of adults and adolescents at different stages of drug development; recommendations regarding dosing, pharmacokinetics, safety, monitoring and ethical considerations.

According to the guide doses have to be selected based on whether the adult dose is fixed or based on body size; dosing should be supported by pharmacokinetic characteristics of the drug, the therapeutic index of the drug and dose- and exposure-response relationships. Pharmacokinetic samples for adolescents should be collected according to the drug development programme to verify exposure in adolescents and adults. In case of body size-adjusted dosing adolescents should receive the same body size-adjusted dose as adults; however if it is fixed dose then a minimum body weight threshold should be defined to prevent adolescents with a lower than average body weight from exceeding adult exposure. While in early drug development long term safety follow up may not be possible the guide recommends sponsors to develop plan for long term safety evaluation where feasible. Under the federal regulations, IRBs reviewing adult oncology clinical trials that allow for the enrolment of adolescents must ensure that the provisions of 21 CFR Part 50, Subpart D (‘Additional Safeguards for Children in Clinical Investigations’) and 21 CFR 50.52 (‘Clinical Investigations involving Greater than Minimal Risk but Presenting the Prospect of Direct Benefit to Individual Subjects’) are satisfied before approving the trials.

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Circulating tumor cells and their future in oncology diagnostic

Circulating tumor cells and their future in oncology diagnostic

Circulating tumour cells (CTCs) are rare tumor cells that have been investigated for diagnostic, prognosis and predictive biomarkers for different types of cancer. CTCs have been described back in 1869. They are not used in clinical practice at the moment, however CTCs were explored in breast, lung, prostate and colorectal cancers.

How rare are CTCs?

There is approximately 1 circulating tumor cell per ml of blood released by primary tumors or metastases that can be detected in peripheral blood.

What types of circulating tumor cells exist in clinical practice?

  1. Treatment based on CTCs used as liquid biopsy: Biopsies are invasive, expensive, time-consuming and potential harmful so using CTCs is one way of avoiding this procedure.
  2. Treatment based on CTC count or CTC variations: This depends on technique used and volume of blood screened.
  3. Treatment based on CTC biomarker expression: Isolating single cell of CTCs could be challenging.

What are the challenges of using circulating tumor cells in cancer screening?

Usage of Cellsearch technique in early non-metastatic cancer have shown low CTC detection rates (5-30% depending on the cancer type). This method is limited to some circulating epithelial cells so it cannot be used wildly. Unfortunately other techniques have not shown better detection rates.

How could CTCs be used as prognostic value?

Analysis of 1944 patients with breast cancer using CellSearch has shown that patients with increased CTCs have poor prognosis and decreased progression-free survival. Also evaluating CTCs count at baseline allows better prognosis of survival. Similar results are observed in patients with metastatic colon cancer, castration-resistant prostate cancer and small cell and non-small cell lung cancer.

CTCs value as prognostic factor was also observed in non-metastatic cancers with similar correlation – the higher amount of CTCs means poor prognosis.

How could CTCs be used in monitoring treatment response?

Studies with patients with metastatic breast cancer have shown that women with high baseline CTC counts, which is reduced after one cycle of chemotherapy have better prognosis than patients where their CTC count is elevated.

While CTCs have great potential as prognostic factor and in monitoring therapy, there are still lots of challenges before their implementation in clinical practise with biggest among them – discovering new methods and techniques for detection of CTCs.

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Circulating tumor cells: clinical validity and utility

Published on 2 July 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

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CircRNA as cancer biomarker and potential therapeutic target

CircRNA as cancer biomarker and potential therapeutic target

Circular RNAs (circRNAs) are class of long, non-coding RNAs, which are very tissue specific. Initially these circRNAs were thought to have no biological function. In the recent research there are more and more evidence that these types of RNA are present in mammalian cells and regulate gene expression by binding to microRNAs and other molecules to inhibit their function.

There also evidence that circRNAs may be involved in development of some diseases like atherosclerotic vascular disease, neurological disorders, prion diseases, osteoarthritis, diabetes, Parkinson’s, Alzheimer, multiple sclerosis, schizophrenia, colorectal cancer, hepatocellular carcinoma, breast cancer and pancreatic ductal adenocarcinoma.

A study shows that circRNAs synthesis is mediated by epithelial mesenchymal transition (EMT). EMT is known to be involved in cell invasion and metastasis. circRNAs have also showed to interact with cerebellar degeneration-related protein 1, which is expressed in the brain and may be connected with Parkinson’s, Alzheimer and brain development.

For example, circ_0067934, which is circRNA, is shown to be overexpressed in oesophageal cancer cells than in normal cells. It is also discovered that this circRNA is involved in tumor development – tumor progression is associated with higher expression of  circ_0067934. Similar case is observed with circ_002059, another circRNA, which is in lower concentrations in gastric cancer in comparison to normal tissue.

All these findings show a promise that circRNA could be used as biomarker and potential therapeutic target. However more research is required to clarify the exact functions of the circRNAs.

Source

CircRNA: a novel type of biomarker for cancer

 

Published on 2 May 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

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Cancer Immunotherapy and Killer Cells

Cancer Immunotherapy and Killer Cells

Cancer immunotherapy is a promising field in drug development because it provides new treatment options for various cancers, especially in combination with standard of care.

Immune system can recognize and eliminate tumour cells and is responsible for targeting most cancers in initial phase. However, cancer cells can escape the immune system.

What are the cytokine-induced killer cells?

Cytokine-induced killer cells (CIK) are mix of activated lymphocytes, including natural killer T cells, cytotoxic T cells and natural killer cells.

Tolerability and Safety

CIK are studied in vitro and in vivo in some pre-clinical studies. Administration of CIK has shown so far minimal side effects and significant toxicity was observed in only small percentage of treated patients. Some of the most common side effects are: fever, headache, fatigue, fever-related chills and rash. Most of them are resolved spontaneously within 24 h or require only symptomatic treatment.

Clinical Trials

  1. Hepatocellular Carcinoma (HCC)

Immunotherapy with CIK cells used in combination with surgical resection or in patients not candidates for hepatectomy prevents recurrence and/or metastasis and increases overall survival.

  1. Renal Cell Carcinoma (RCC)

Current studies have shown that CIK treatment may prevent recurrence/metastasis and improve overall survival of patients with advanced RCC.

  1. Non-small Cell Lung Cancer (NSCLC)

Current data indicates that CIKA may significantly prolong time to progression in patients with late-stage NSCLC.

  1. Gastric Cancer (GC)

Current research shows that CIK could be used as adjuvant treatment to prolong the survival of patients with stage II – III gastric carcinoma.

  1. Other Solid Tumors

CIK were studied also in breast cancer, ovarian cancer and soft-tissue sarcomas. While the results in breast cancer and ovarian cancer are promising, the ones in soft-tissue sarcomas are inconclusive.

There is ongoing research in adoptive immunotherapy where patients are administrated tumor-specific cytotoxic T cells to stimulate patient’s immune system and the cells are able to recognize and kill tumors.

Challenges in CIK therapy

  1. There is no standardized protocol for generating CIK cells.
  2. Dosage is not determined yet.
  3. Current studies are too heterogenic to allow clear conclusions about outcome.
  4. CIK are generated under GMP conditions.

While current results are promising more studies are required to determine the safety and efficacy of CIK.

Source

Cancer Immunotherapy with Cytokine-Induced Killer Cells

Published on 2 April 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

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