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

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Practical Clinical Trials, Issue 4 2017

Practical Clinical Trials, Issue 4 2017

We are happy to release out annual edition of Practical Clinical Trials magazine for 2017. It features materials which were published on our web site in 2017. It includes some very exciting reviews on latest trends in oncology therapy and diagnostics and lots of ethical challenges in clinical trials.
Thank you for downloading our magazine and we hope you will enjoy reading it.

Download free magazine: Practical Clinical Trials, Issue 4 2017

 

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MicroRNAs and cancer

MicroRNAs and cancer

MicroRNAs (miRNAs) are non-coding RNAs, which are used generally to down-regulate gene expression from messenger RNA (mRNA) by binding to it. miRNAs are getting popular in potential application in cancer therapy. They could be used either to replace tumour suppressive miRNA lost in cancer or to inhibit oncogenic miRNA, which is overexpressed in cancer.
miRNAs are small single-stranded RNAs, usually consistent of 18-26 nucleotides. Mature miRNAs have RNA-induced silencing complex (RISC), which allows them to target many mRNAs. They use this mechanism to down-regulate mRNA. According to some predictions – each miRNA could regulate up to 200 individual mRNAs.
In cancer tumours use different mechanisms to overcome the control of the normal cells. The role of miRNAs was first studied in 2002 in chronic lymphocytic leukaemia. There are several well-studied miRNAs that have oncogenic or tumour suppressive functions. Currently there are over 2 500 known miRNA but the functions of many of them as still unknown.
However there are some limitations in miRNA application:
  • There should be very careful selection of the target as one miRNA could interact with many mRNAs and affect different processes.
  • Current miRNA process involves targeting or imitating specific miRNA, which is involved in cancer related process. Therapeutic targeting may need miRNA to act as an oncogene or as a tumour suppressor.
Approaches that could be used in oncology
  • Loss of cell-cell adhesion allow cancer cells to enter blood-stream and reach distant sites. There are miRNAs that target epithelia-to-mesenchymal transition, which is critical regulator of metastasis. There are artificial miRNAs that have shown to inhibit transformation, migration and invasiveness in vitro and suppress tumourigenicity in vivo.
  • Targeting cancer cells and blocking their activity is a well-known strategy. There are many miRNAs involved in the process and currently over 40 miRNAs were identified. Many are involved in cell cycle suppression.
  • miRNAs could be used to overcome chemotherapy resistance. There are evidence that chemotherapy resistance is result of epigenetic modifications and they are controlled by miRNAs. There is research to use miRNAs for delivery agents in combination of DNA damaging agents or chemotherapy.
  • miRNAs are shown to be involved in tumour immune response and this makes them attractive potential therapeutic agent that can modulate immune response and suppress tumour metastasis.
While miRNA provide exciting new opportunities in oncology, there are still many unknown potential interactions and side effects which need to be studied. RNA technologies are definitely an exciting field to follow in the future.
Source
Exploiting microRNAs As Cancer Therapeutics

 

Published on 4 January 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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Clinical research and brain metastases: the unique challenges

Clinical research and brain metastases: the unique challenges

According to estimates in US approximately 6 – 14% of newly diagnosed patients will develop brain metastases. Almost 45% of patients with lung cancer will develop brain metastases, based on statistical data. Unfortunately there is a poor prognosis for patients with brain metastases. Often by the time they are identified they are no operable and the treatment options are quite limited.

What are the challenges in research?

  • Brain metastases are usually secondary tumour site and so far the research is focused on preventing and treating primary tumours.
  • The unique nature of the brain and its interactions with cancer cells make it difficult to study with in vitro models. The in vivo models also have their limitations – high mortality rates of lab test mice.
  • Mouse models may not be adequate to reflect human brain metastases.

Why the brain is different?

Brain has highly specialized cells, neurons, which allow signals to be transmitted and received throughout the whole body. One of the specific features of the brain is blood-brain barrier (BBB), which controls the flow to the brain and vice versa. Not surprisingly then the first thing the cancer cells have to do when they reach the brain is to pass through the blood-brain barrier. When cancer cells arrive at blood-brain barrier they have to arrest the blood vessels first, which is quite complex process. So far it is observed that cancer cells managed to penetrate blood-brain barrier by passing between the cells, but they can also kill the endothelial cells of the BBB. Once they penetrate BBB cancer cells use different mechanisms to spread. Current data shows that the mechanism that they will use depend on the primary tumour (breast, lung, etc.). Brain cells, known as astrocytes, are the first one to attack cancer cells and try to neutralise them, however cancer cells block astrocytes. High jacking astrocytes also allow cancer cells to develop chemotherapy resistance. Brain is also protected by immune system, cells known as microglia. Microglia originates from bone marrow and can produce macrophages which can eliminate cancer cells. How cancer cells overcome microglia is still unknown due to difficulties to design such experiments.

There are still many unknown in brain metastases mechanism and real challenges in studying these mechanisms.

Source

Brain metastasis: Unique challenges and open opportunities

Published on 6 December 2017

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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CRISPR – Cas9: glimpse into the future of gene editing and oncology therapy

CRISPR – Cas9: glimpse into the future of gene editing and oncology therapy

Gene editing techniques are exciting for scientist and oncologists who hope that they will give a new approach in treating cancer and even opportunity to eradicate it all. The idea of gene editing has been around for some time, however so far there was no technique that is relatively safe, practical and cost-effective. The discovery and development of CRISPR – Cas9 is a major step forward in this area.
What is CRISPR – Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat – associated protein 9)?
This is a new technique that uses single guided RNA and Cas9 endonuclease, which could target specific parts of DNA and initiate DNA repair. Of course, this is a very broad explanation of a complex mechanism, which requires significant knowledge in genetics.
Why everyone is excited about CRISPR – Cas9?
This new technique has some advantages over other similar methods.
  • This method works on level single guided RNA and RNA-DNA interaction – in the prospect of oncology application this allows known oncogenes to be targeted and “switched off”, it also could be used to repair DNA and oncogenes to be removed. It provides opportunity to target cancer cells and “repair” them.
  • Single guided RNA is a short fragment of RNA which makes it easy to synthesis and clone.
  • The data so far shows low cytotoxicity.
  • The short fragments of RNA allow very specific and efficient targeting.
  • Synthesis of short RNA fragments is cost-effective.
  • The manipulation is easy and rapid, which makes it more practical in comparison to other techniques.
What are the possible applications in oncology?
CRISPR – Cas9 gives new hopes to oncologists to provide them with new tool that could help them tackle challenges.
  • One of the main reasons for chemotherapy failure is that patients develop resistance to the therapeutics. Gene editing could be used to repair such mutations which cause resistance to chemotherapy.
  • Gene editing could be a way to block known oncogenes or to remove them. It also could allow repair of cancer calls on DNA level.
  • It could be used to supress tumour cells growth and spread.
  • Many cancers are caused by infection with oncogenic virus and this technique could be used to inactivate these viruses. Example for such type of viruses is Human Papilloma Virus and its role in cervical cancer; Epstein – Barr virus and nasopharyngeal carcinoma; and Hepatitis B and C and liver cancer.
  • This method could be used to improve radiotherapy insensitivity which is observed in some tumours. This could be achieved by repairing these genes that cause the insensitivity.
  • CRISPR – Cas9 could be used to target specific tissues which could be major breakthrough in treating rare oncology diseases affecting soft tissues.
What are the challenges?
  • There are still many knowns regarding the long-term application of this method.
  • Some new reports show that this technique could generate additional undesired mutations.
CRISPR – Cas9 provides new opportunities but also challenges. The success of this technique could change the future of cancer treatment.
Source
CRISPR – Cas9 therapeutics in cancer: promising strategies and present challenges

 

Published on 
3 Nov 2017
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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Immunotherapy and oncology: challenges of early development

Immunotherapy and oncology: challenges of early development

While the classic chemotherapy agents are cytotoxics, which do not have specific target, the new approach in oncology drug development is focused on immunotherapy, where the new compounds target specific molecular targets.
But what are the challenges in immuno-oncology drug development?
  • Unlike classic cytotoxics immunotherapy requires specific patient population, which is selected based on strong biological rational and predictive biomarkers. However, the data that is available currently regarding biomarkers is very limited.
  • Different tumour types respond in a different way to immunotherapy. Tumour heterogeneity is another challenge.
  • Because these new immunotherapy agents have new mechanisms of action it is critical to select carefully the endpoints. Failure to do so may give false inefficacy results in early stage.
  • Standard radiology assessments of tumour response (such as widely used RECIST criteria) may not be the best to evaluate these new agents. This led to the development of new assessments: Choi criteria, mRECIST and PERCIST. Proper evaluation of the tumour response is important not only to avoid exposing patients on unnecessary toxicity if the treatment is not efficient in them but also continue treatment for patients who benefit from the treatment and have had pseudo-progression.
  • New toxicity profiles – there are new toxicity associated with the immunotherapy, which are still unknown – for example, sepsis, autoimmune reactions, etc. Often such toxicities were not detected in preclinical research.
  • Optimal dose could be different in immunotherapy – the new agents have different mechanisms of action and lower doses could trigger the required response. The classic concept of dose was to be administrated the highest possible dose, which does not trigger unacceptable toxicity.
The new challenges that the immuno-oncology establish require new designs of the clinical trials, which will take into consideration the complexity of the new treatment agents and the therapeutic area.
Source
Immuno-Oncology: The Third Paradigm in Early Drug Development
Published on 2 August 2017
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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