Is it possible to have an anti-cancer therapeutic vaccine

Is it possible to have an anti-cancer therapeutic vaccine

There are many observations in melanoma lesions where the immune system is able to act against the tumours and usually this is a sign of a good prognosis. However, over time the balance is shifted in favour of the tumours.

All this suggests that vaccination for cancer immune therapy, which targets specific tumours could be a possibility in such cases. Current vaccination in cancer is primary a therapeutic intervention rather than prevention like the case with infections diseases. Preventive vaccination against cancer is not possible yet in humans.

But before we consider that type of vaccination there is a need to identify different vaccination strategies for cancer immune therapy and also identification of effective mechanisms used by the immune system.

Hybrid cell vaccination is one of these strategies that use the patient’s tumour cells as antigen and turn them into potent T cell stimulators by fusion with antigen-presenting cells (APCs) such as dendritic cells (DCs).

There are over 250 tumour-associated T cell epitopes derived from about 60 different proteins and majority of the antigens were identified for melanoma and are MHC class I-restricted. Some of these antigens identified in melanoma were later on identified in other tumours.

Cytotoxic T cells with specificity for differentiation antigens are not supposed to exist, as they should have been eliminated during the establishment of self-tolerance. However, they are observed in cancer patients and even healthy individuals. One potential explanation is that these antigen receptors might be of low avidity and in this case the T cells will also have too low efficiency to eliminate the tumour cells.

T cell epitopes specific to tumour cells would be ideal for immune therapy, however very few have been identified in cancer patients so far.

 

What kind of clinical data is available?

There are number of clinical trials using hybrid cell vaccination strategy that have shown promising results although the patient population were mostly stage IV. A vaccine prepared by fusion of autologous tumour cells with allogeneic activated B cells and given intracutaneously or intradermally have cause turmour response in 3 our of 13 patient with renal cell carcinoma and in 2 our of 16 patients with metastatic melanoma while 5 others had stable disease. Interestingly stable disease was maintained for more than 2 years for some patients.

Another study with allogeneic DCs and autologous tumor cells was completed with 17 patients with metastatic renal cell carcinoma. 4 of the patients had complete response; 2 patients – partial responses and 1 patient – mixed response. Some of the common side effects observed in these studies are: erythema at the sites of inoculation, some cases of fever and others of strong but temporal perspiration. Generally, toxicity is low.

While the results are promising more information is needed to support therapeutic use of hybrid cell vaccination.

Source:

Cancer Immune therapy: Hybrid Cell Vaccination for Cancer Immune Therapy

Published on 1 Oct 2019

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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The role of microRNAs in human diseases

The role of microRNAs in human diseases

It is very common that microRNAs are overexpressed or inactivated in human diseases. The best approach in such cases is to either target the overexpressed microRNA to inactivate it or replace the inactive microRNA.

But let’s first review what is microRNA and what is their role.

MicroRNAs are small noncoding RNAs that are approximately 20-25 nucleotides in length. Most microRNAs are the same in different animal species, which underline the importance of microRNA in the evolution. The process of inactivating the microRNAs does not require perfect complimentary recognition of the target, because only the 6 to 8 nucleotides in the 5’ portion of microRNAs is sufficient to trigger interaction. Also single microRNA can regulate multiple mRNAs. More importantly the ability of microRNAs to influence entire network of gene involve in common cellular process provide great therapeutic opportunity.

miR-122 and hepatitis C

miR-122 is a microRNA expressed in liver, which helps hepatitis C virus (HCV) to replicate once it reaches the liver. It’s natural role in the liver is to regulate its metabolic functions – cholesterol homeostasis, fatty acids and lipid metabolism. miR-122 is conservative to HCV across all genotypes and subtypes. A clinical study using SPC3649, 15 nucleotide phosphorothioate oligonucleotide, has shown positive results in monkeys.

miR-33 and atherosclerosis

One of the potential mechanisms of eliminating LDL cholesterol involves efflux from the macrophages in atherosclerotic vascular lesions to circulating HDL, which will help to be excreted into the faeces. Studies have shown that miR-33a/b inhibit the expression of the cholesterol transporter ABCA1, which result of increased levels of atheroprotective plasma HDL. Mice models have shown that inhibition of miR-33 raise plasma HDL and support lowering of LDL.

miR-221 in hepatocellular carcinoma

miR-221/222 cluster has been reported to be over-expressed in multiple cancers, including hepatocellular carcinoma. miR-221 is reported to be expressed at a higher level than miR-222. The reason for the over-expression is unknown, however it was shown in human studies that the level of serum miR-221 in patients with hepatocellular carcinoma correlate with tumour size, stage and patient survival. This makes miR-221 important target in cancer research.

MicroRNAs definitely provide unique opportunity in drug development. Different studies show that microRNA inhibitors can have effect on different diseases.

Source

Therapeutic modulation of microRNAs

Published on 2 Sep 2019

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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Adopting orphan drugs in different therapeutic areas

Adopting orphan drugs in different therapeutic areas

What happens if a newly developed drug fails in the tested indication?

Very often such drugs are abandoned if the developers think they will not be able to be used for different indications or therapeutic areas. In such cases these drugs are classified as ‘orphaned drugs’.

Where the term ‘orphaned drug’ comes from?

The focus of drug development is shifting towards diseases that affect smaller amount of the population, also known as rare or ‘orphan’ diseases. In USA a disease is considered ‘orphan’ if affects less than 200 000 people or roughly 1 per 1500 people. The term ‘orphan drug’ refers to drugs used to treat orphan diseases and its derived from legislation like Orphan Drug Act of 1983.

Not surprisingly oncology is viewed as one of the major therapeutic area where orphan drugs are used because more and more evidence suggest that cancer is a collection of orphan diseases.

Vicus Therapeutics has developed a model which allows adoption of such orphan drugs for new cancer indications.

Step 1:  Hierarchical Network Algorithm (HiNET) – This is an algorithm that allows modelling of the disease by evaluating tissue energetics, homeostatic control and biochemical pathways.

Step 2: Drug Selection: In this step it is used a data base which contains information for off-patent drugs, their target and human efficacy data in similar diseases, potential adverse events and pharmacokinetic profiles.

Step 3: Due to the complexity of cancer rarely one single drug could be used, therefore the model created potential treatment regimens.  Then the suggested regimens are evaluated for their potential safety and efficacy.

The use of such models in repurposing the orphan drugs is a novel and smart way of speeding up drug development process and identifying new therapies for rare diseases which in many cases have no treatment options.

Source

Adopting orphan drugs: developing multidrug regimens using generic drugs

Published on 4 July 2019

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 trial design and patients with brain metastases

Clinical trial design and patients with brain metastases

The most common spread of metastatic solid tumours in central nerve system (CNS) is as parenchymal brain metastases or as leptomeningeal disease (metastases in brain membrane or spinal cord). Because the brain is protected by blood-brain barrier many drugs in standard dose will not achieve the required concentrations to be effective in CNS. Some anti-cancer drugs, however, do not cross blood-brain barrier at all but activate lymphocytes that can penetrate to CNS; while other drugs do not have effect on CNS.

For many experimental anti-cancer therapeutics there may be not sufficient information regarding their activity on CNS. As a result if the studied drugs do not have effect on CNS patients with brain metastases will progress quickly and this may affect the overall outcome of the clinical trials. On the other hand if the anti-cancer drugs have CNS activity and patients with brain metastases are excluded from the clinical trials there will be no information on drug activity on CNS and patients will miss new treatment option.

What types of clinical trial designs are possible for patients with CNS disease?

Design 1 – if the drug is considered unlikely to have CNS activity or efficacy

There are 2 possible designs to overcome the challenges above:

  • Exclude patients with CNS disease
  • Exclude patients with untreated or unstable CNS disease – CNS disease has to be either asymptomatic on stable dose of corticosteroids or off corticosteroids.

Design 2 – if the drug is considered likely to have CNS activity or efficacy

  • Permit untreated CNS metastases
  • If untreated CNS disease is measurable, mandate that these lesions be captured as target lesions
  • Define whether a growing CNS lesion previously treated with radiotherapy is permissible as a target lesion
  • Standardise CNS imaging frequency
  • Define if symptomatic, or if steroids or anticonvulsants permitted initially, or later
  • Specify bicompartmental endpoints and action if progression is observed in one but not both compartments
  • For randomised studies, stratify according to:
  • Whether CNS disease is present or absent
  • Whether CNS disease is treated or untreated
  • If treated, whether CNS progression has occurred

Design 3 – if there is minimum information on drug activity on CNS

Appropriate for phase 1 studies

This model includes dose escalation until the optimum dose is achieved. Then it is followed by molecularly or histologically defined efficacy expansion cohorts; food effect and drug-drug  interaction sub-studies and CNS metastases sub-study.

Appropriate for phase 2 and 3 studies

  • Initially permit only absent or treated and non-progressing CNS metastases in general trial population
  • Permit separate single-arm early CNS cohort with defined number of patients with measurable untreated or progressing CNS disease with separate early efficacy analysis such as CNS objective response
  • Minimise risk in this early CNS cohort by only allowing in asymptomatic cases
  • Modify protocol (as either amendments or following pre-written decision pathways) as data emerge to be like either scenario A or scenario B

CNS progression is a big challenge in treating patients with metastatic solid tumours. New approaches are required to assess when patients with CNS disease could be appropriately included or excluded from clinical trials.

Source

Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group

Published on 1 Oct 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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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.

Source

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.

Source

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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