Welcome to the Cancer Bioengineering Group!

It is time for a full group presentation here at the blog! Throughout the month we shared about our group members and their research focus on Twitter. Now, we would like to share more about the group here and invite you to keep following us on social media. 

The Cancer BioEngineering Group is a research group led by Dr Olga Piskareva at the Royal College of Surgeons in Ireland. The group has 6 PhD students developing research projects around neuroblastoma biology.  

Our projects address topics related to neuroblastoma microenvironment, cell interactions, tumour resistance and the development of new therapies. To do that we use 3D in vitro models, identify immunotherapeutic targets and evaluate extracellular vesicles.  

We are a dynamic group proud to be engaged in research, science communication and patient involvement. We do that through different initiatives.  

We support and collaborate with several neuroblastoma charities around Ireland and internationally such as the Conor Foley Neuroblastoma Foundation, the National Children Research Centre, the Children’s Health Foundation Crumlin and the Neuroblastoma UK. Moreover, our projects are funded by the Irish Research Council in partnership with these charities and by RCSI StAR PhD programmes.  

We promote neuroblastoma awareness through different activities. For instance, last September at the Childhood Cancer Awareness month we promoted a hiking challenge to raise money and increase awareness of neuroblastoma. We hiked for 30km at Wicklow mountains in a day and raised over € 2,000 for neuroblastoma research charities.  

We are also present in social media, creating content in the form of blog posts and tweets to share the science we are doing.  

We are always happy to answer questions and interact with the public. Follow us on our social media channels and read our blog to know more about us and our research.  

Thanks for reading and we go ahead with neuroblastoma research! 

Written by Luiza Erthal

#AskLuiza: How Does The Microenvironment Influence Neuroblastoma Cells?

Understanding how tumour cells interact with the other cells in the body is crucial for an effective treatment. Moreover, it can help to identify patterns that are exclusive of tumour cells to be a target in treatment.

The interactions of tumour cells with the surrounding tissue, the microenvironment, affects chemotherapy sensitivity, immune cells recognition and expression of molecules on the cell surface, to only cite a few interferences.

This is particularly crucial in metastatic cells, which are cells that have spread to other parts of the body coming from the primary tumour location. Specifically, for neuroblastoma half of patients with high-risk disease present a metastatic tumour at the diagnosis. In addition, one of the organs that are mostly populated by metastatic neuroblastoma cells is the bone marrow.

A review paper recently published address some important aspects about the interactions between neuroblastoma cells, bone and bone marrow resident cells1. This review argues in favour of understanding these interactions to search for new targets for therapy.

However, neuroblastoma cells proved to be difficult to characterise due to dynamic changes induced by external stimuli. Therefore, neuroblastoma cells change upon exposure to the bone marrow microenvironment.

The authors present some studies showing that neuroblastoma cells infiltrating the bone marrow express receptors for small proteins called chemokines that induce cell adhesion in the bone marrow. On the contrary, the cells did not present on their surface molecules that stimulate the immune system recognition. Therefore, they are naturally invisible to the action of this system.

Moreover, it has been shown that metastatic tumour cells release extracellular vesicles expressing GD2. These vesicles have an important role in cell-cell communication and the GD2 is a marker exclusive of neuroblastoma cells. Thus, it facilitates the identification of metastatic cells.

These alterations on neuroblastoma cells surface after they interact with bone marrow cells may facilitate the invasion and spread of the tumour. Thus, looking closely to that may help to develop more effective treatments for neuroblastoma.

At the Cancer Bioengineering Research Group, many of our projects are related to tumour resistance, cell interaction and the tumour microenvironment. These three aspects are very important to understand neuroblastoma at the tissue level. We study them and expand this research to applied projects aiming at the development of new therapeutic modalities.

For instance, we are currently evaluating the effect of extracellular vesicles from different neuroblastoma cell lines in the induction of proliferation and increased viability. Moreover, we are studying the interaction of neuroblastoma cells with immune cells such as macrophages. Finally, we are also identifying targets to develop an anti-tumour nucleic acid-based vaccine against neuroblastoma.

We go from basic to applied research interconnecting the findings and expanding the understanding of neuroblastoma biology. Ultimately, we aim to improve treatment and quality of life for patients.

Written by Luiza Erthal

References

1.         Brignole, C. et al. Bone Marrow Environment in Metastatic Neuroblastoma. Cancers 13, 2467 (2021).

#AskLuiza: Is there any vaccine to treat or prevent neuroblastoma relapse?

Anti-cancer vaccines teach the body’s immune system to identify and attack tumour cells. They are a type of immunotherapy and can be used to treat cancer or prevent tumour recurrence. Therefore, they are typically used in patients that have already received other treatments such as surgery, chemotherapy or radiotherapy.

Although anti-cancer vaccines have been gaining more attention over the years, few are being developed for paediatric tumours. From 594 clinical trials in neuroblastoma at clinicaltrials.gov, only 12 active trials are evaluating vaccines. Furthermore, these vaccines are still considered investigational products. They do not have the approval for use granted by health authorities. Therefore, these drugs are available for patients that enter into clinical trials.

An example of these vaccines is the bivalent vaccine for high-risk neuroblastoma developed in the Memorial Sloan Kettering Cancer Center in the US, collaborating with the biopharmaceutical company Y-mAbs Therapeutics. This vaccine is called bivalent because it has two proteins specifically present on the surface of neuroblastoma cells.

The rationale behind the treatment using this vaccine is that the body will be stimulated to produce antibodies against these two proteins. These antibodies will recognise and attach to neuroblastoma cancer cells, thus signalling to the immune system that these cells need to be eliminated.
A phase II trial evaluates vaccine efficacy in 374 patients who received seven subcutaneous injections of the vaccine in combination with an oral intake of an adjuvant, called β-glucan, that boosts the immune system1. The adjuvant intake started either on the first vaccine injection or on the third injection every two weeks until the end of the vaccine schedule. The study aims to analyse the anti-tumour effect of the vaccine and the immune response generated by the vaccine plus β-glucan therapy. The study is estimated to be completed by 2023.
The trials active for neuroblastoma vaccines are phase I or II. After these phases, there are still phases III and IV to complete the evaluation and continue monitoring these therapies. Therefore, in a few more years, we will know if neuroblastoma vaccines will be successful or not.

Written by Luiza Erthal

Reference

1.         Memorial Sloan Kettering Cancer Center. Phase I/II Trial of a Bivalent Vaccine With Escalating Doses of the Immunological Adjuvant OPT-821, in Combination With Oral β-glucan for High-Risk Neuroblastoma. https://clinicaltrials.gov/ct2/show/NCT00911560 (2021).

#AskLuiza: What is the progress in DMFO therapy trials?

Neuroblastoma relapse is one of the greatest challenges to complete cure for children with high-risk disease. At least 40% of high-risk neuroblastoma patients will experience cancer relapse 4 years after intense treatment, which includes a combination of chemotherapy, surgery, irradiation and the self-transplantation of stem cells (consolidation therapy). 

To overcome this problem improved maintenance therapy is needed. These are therapies administered to patients after the end of the initial treatment to prevent tumour relapse. Frequently, maintenance therapy for neuroblastoma includes immunotherapies such as antibodies against GD-2 and cytokines and 13-cis-retinoic acid. Although these therapies have some positive effects, the rate of relapse is still high.  Therefore, other options to prevent relapse are needed.  

Recently, a phase II clinical trial evaluated the effect of Difluoromethylornithine (DFMO) on event-free survival (EFS) and overall survival (OS) of high-risk neuroblastoma patients1Event-free survival means the length of time that the patient remains free of cancer after the end of treatment, while overall survival means the length of time that the patient is alive after the diagnosis or the start of treatment. The measurement of event-free survival and overall survival provides a good indication of the treatment effect.  

In this clinical trial report the therapy efficacy on 81 patients that received immunotherapy treatment with dinutuximab and started DFMO maintenance therapy at least 120 days after completion of treatment were compared to the efficacy (based on medical records) from a group of 76 patients that got the same treatment but without the maintenance with DFMO.  

DFMO inhibit the ornithine decarboxylase pathway, which is related to cell growth and decreased cell death, thus preventing cells to become cancerous and tumour progression. The results demonstrated that maintenance therapy with DFMO provided 85% of 5-year event-free survival compared to 65% for no-DFMO maintenance therapy, and 95% 5-year OS compared to 81% no-DFMO therapy2.  

In conclusion, this study results suggest a benefit provided by the DFMO therapy in preventing neuroblastoma relapse. The researchers suggest that early therapy with DFMO may further improve these results.  Therefore, more clinical trials evaluating this possibility are being conducted3,4.  

Written by Luiza Erthal

References 

1. SaulnierSholler, G. A Phase II Preventative Trial of DFMO (Eflornithine HCl) as a Single Agent in Patients With High Risk Neuroblastoma in Remission. https://clinicaltrials.gov/ct2/show/NCT02395666 (2020). 

2. Lewis, E. C. et al. A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high‐risk neuroblastoma. Int. J. Cancer 147, 3152–3159 (2020). 

3. SaulnierSholler, G. Phase II Trial of Eflornithine (DFMO) and Etoposide for Relapsed/Refractory Neuroblastoma. https://clinicaltrials.gov/ct2/show/NCT04301843 (2021). 

4. SaulnierSholler, G. NMTT- Neuroblastoma Maintenance Therapy Trial Using Difluoromethylornithine (DFMO). https://clinicaltrials.gov/ct2/show/NCT02679144 (2021). 

#AskLuiza: What is new in immunotherapy clinical trials for neuroblastoma?

Immunotherapies are treatments that stimulate the patient’s immune system to help it to fight cancer. This type of treatment is gaining more attention in neuroblastoma due to the possibility to combine it with other therapies, potentially, generating fewer side effects.

Clinical trials are research protocols performed in patients to evaluate whether a new treatment is safe and effective. This type of research can also compare standard treatments with new treatment options as well as investigate new combinations of drugs. Clinical trials occur in phases comprising phase I (safety), phase 2 (safety and efficacy), phase 3 (safety, efficacy and comparison with standard treatments for the specific disease).

According to a search performed on November 14th, 2021, there are 594 clinical trials for neuroblastoma at clinicaltrials.gov, a clinical trial database from the United States (US). From these, 173 are recruiting or active trials and 15 are related to immunotherapies. Generally, these are initial trials evaluating treatment combinations using chemotherapy, cell transplants and immunotherapy, including antibodies and vaccines.

Trials for antibodies

The most explored target for immunotherapy in neuroblastoma is the GD2, a molecule present in the surface of neuroblastoma cells that can be used to combat the tumour. Indeed, antibodies that bind to GD2 called dinutuximab and naxitamab are approved for use in the US to treat neuroblastoma1,2.

A clinical trial in the US and Canada is recruiting patients to evaluate the combination of dinutuximab with another antibody called Magrolimab in patients with neuroblastoma that do not respond to or come back after treatment3. This is an initial trial (Phase 1), which aims to determine the best doses and side effects of this combination.

Racotumomab, an antibody that binds to N-glycolyl GM3, a molecule that is highly expressed in the surface of neuroblastoma cells, is being evaluated in high-risk neuroblastoma5. The study aims to determine the immune response generated by the drug and the related toxicity.

Trials for vaccines

A trial from Dana-Farber Cancer Institute is recruiting patients to study the GVAX Vaccine and its combination with the antibodies, nivolumab and ipilimumab, that stimulates T-cells to attack the cancer 6. The vaccine is produced with neuroblastoma cells from the patient. The study will evaluate the dose and safety of the combination treatment.

Another trial is evaluating the use of a modified neuroblastoma cell vaccine in combination with low doses of chemotherapy (Cytoxan/Cyclophosphamide)7. A vaccination scheme comprising 8 doses of vaccine and cycles of oral chemotherapy is planned and patients will be closely monitored through the vaccination period to evaluate side effects and disease status. This study is ongoing and will follow the patients for 15 years after completing the vaccination scheme.

Trials for cell therapy

A trial evaluating the use of modified T-cells (CART-T-cell) to recognise GD2- neuroblastoma cells in combination with chemotherapies (cyclophosphamide and fludarabine) and an antibody (Pembrolizumab) is ongoing8. The combination is based on previous studies that have demonstrated the longer time presence of CAR T-cell in the blood of patients after intravenous infusion of chemotherapy. Moreover, the antibody will help to stimulate the patient immune system. The trial aims to determine the highest dose possible for the combination treatment generating fewer side effects.

Another Phase I immunotherapy trial for neuroblastoma aims to compare the treatment with dinutuximab and lenalidomide (drugs that support the immune system) and Natural Killer (NK) cells from the patient9. The NK cells can kill cancer cells while the two immunotherapeutic drugs activate the NK cells. This study will determine the safest dose of cells to be used in combination with the drugs.

Conclusion

Considering some of the clinical trials in progress that uses immunotherapy to treat neuroblastoma, we can conclude that this therapy modality holds great promise to advance and potentially serve as a new treatment option to improve neuroblastoma patients’ survival and quality of life.

Written by Luiza Erthal

References

1.         Drugs Approved for Neuroblastoma – National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/drugs/neuroblastoma (2011).

2.         Memorial Sloan Kettering Cancer Center. Expanded Access Use of Naxitamab/GM-CSF Immunotherapy for Consolidation of Complete Remission or Relapsed/Refractory High-Risk Neuroblastoma. https://clinicaltrials.gov/ct2/show/NCT04501757 (2021).

3.         National Cancer Institute (NCI). Phase 1 Trial of Hu5F9-G4 (Magrolimab) Combined With Dinutuximab in Children and Young Adults With Relapsed and Refractory Neuroblastoma or Relapsed Osteosarcoma. https://clinicaltrials.gov/ct2/show/NCT04751383 (2021).

4.         Memorial Sloan Kettering Cancer Center. Hu3F8/GM-CSF Immunotherapy Plus Isotretinoin for Consolidation of First Remission of Patients With High-Risk Neuroblastoma: A Phase II Study. https://clinicaltrials.gov/ct2/show/NCT03033303 (2020).

5.         Laboratorio Elea Phoenix S.A. Open-label, Multicenter, Phase II Immunotherapy Study With Racotumomab in Patients With High-risk Neuroblastoma. https://clinicaltrials.gov/ct2/show/NCT02998983 (2021).

6.         Collins, N. B. A Phase 1 Study of Combination Nivolumab and Ipilimumab With Irradiated GM-CSF Secreting Autologous Neuroblastoma Cell Vaccine (GVAX) for Relapsed or Refractory Neuroblastoma. https://clinicaltrials.gov/ct2/show/NCT04239040 (2021).

7.         Heczey, A. A Phase I/II Study Using Allogeneic Tumor Cell Vaccination With Oral Metronomic Cytoxan in Patients With High-Risk Neuroblastoma (ATOMIC). https://clinicaltrials.gov/ct2/show/study/NCT01192555 (2021).

8.         Heczey, A. Autologous Activated T-Cells Transduced With A 3rd Generation GD-2 Chimeric Antigen Receptor And iCaspase9 Safety Switch Administered To Patients With Relapsed Or Refractory Neuroblastoma (GRAIN). https://clinicaltrials.gov/ct2/show/NCT01822652 (2021).

9.         New Approaches to Neuroblastoma Therapy Consortium. A Phase I Dose Escalation Study of Autologous Expanded Natural Killer (NK) Cells for Immunotherapy of Relapsed Refractory Neuroblastoma With Dinutuximab +/- Lenalidomide. https://clinicaltrials.gov/ct2/show/NCT02573896 (2021).

September is Childhood Cancer Awareness Month!

Today marks the start of Childhood Cancer Awareness Month.

Three girls fountain in Mainz Germany 

The cause of childhood cancers is believed to be due to faulty genes in stem cells that give rise to nerves, skin, blood and other body tissues. For some unknown reasons, the faulty genes can sit quiet and show their ‘bad’ character after birth and programme the cells into cancer cells.
So, there is no evidence that links lifestyle or environmental risk factors to the development of childhood cancer, which is opposite to many adult’s cancers.

Every 100th cancer patient is a child. Cancer is the 2nd most common cause of death among children after accidents.

Children are not little adults and so their cancer. Some childhood cancers have a good outlook and successful protocol of treatments. However, some of the cancers do not respond to the known drugs, or if respond cancer cells find the way to develop resistance and come back being more aggressive. Among theme are some forms of brain tumours, neuroblastoma and sarcomas; cancers developing in certain age groups and/or located within certain sites in the body, along with acute myeloid leukaemia (blood cancer). Children with a rare brain cancer – diffuse intrinsic pontine glioma survive less than 1 year from diagnosis. Children with soft tissue tumours have 5-year survival rates ranging from 64% (rhabdomyosarcoma) to 72% (Ewing sarcoma). Less than50% of children with the aggressive form of neuroblastoma will live beyond 5 years with current treatment strategies.

For majority of children who do survive cancer, the battle is never over. Over 60% of long‐term childhood cancer survivors have a chronic illness as a consequence of the treatment; over 25% have a severe or life-threatening illness.

The most common types of childhood cancer are:

  • Leukaemia and lymphoma (blood cancers)
  • Brain and other central nervous system tumours
  • Muscle cancer (rhabdomyosarcoma)
  • Kidney cancer (Wilms tumour)
  • Neuroblastoma (tumour of the non-central nervous system)
  • Bone cancer (osteosarcoma)
  • Testicular and ovarian tumours (gonadal germ cell tumours)

Please see a short video The Childhood Cancer Ripple Effect created by St. Baldrick’s Foundation.

A new, three-dimensional approach to cancer research

Appeared in today’s Irish Times. Lovely crafted by Dr. Vanesa Martinez

Although the discovery could be applicable in principle to any a solid tumour, Dr Piskareva’s target is neuroblastoma, a relatively common child cancer which affects a specific type of nerve cells in unborn children. “It’s quite aggressive and unfortunately there are many children who have metastasis when they are diagnosed, and this is the most challenging group to treat.”

Irish Times, 31 May 2018

https://www.irishtimes.com/news/science/a-new-three-dimensional-approach-to-cancer-research-1.3505347

Childhood and Cancer

Walking in Mainz last week I saw a lovely fountain capturing 3 girls under umbrellas (Drei-Mädchen-Brunnen) at the ball square. This fountain was built between two Catholic girl’s schools symbolising the separate education and happy childhood. It has charmed me and reminded rainy days in Ireland and how this fountain may fit any park or square in Dublin.

My second look at the picture gave me another perspective. This sculpture could illustrate not only happy childhood but also the protection we can give to children with cancer being their umbrellas. As September is childhood cancer awareness month, I am picking this picture to support this call. Raising awareness about childhood cancer we help to make their dreams come true. Dreams for better treatment, better quality of life full of love ahead through better funding of childhood cancer research and access to innovative treatments.

Three girls fountain in Mainz Germany

What lessons have been learnt?

Today is the final day of the Third International Cancer lmmunotherapy Conference. The meeting was run at the Rheingoldhalle Congress Center in Mainz/Frankfurt, Germany from September 6-9, 2017. More than 500 people attended this meeting.

The focus of the scientific program was on “Translating Science into Survival”. Talks covered the challenging areas in cancer immunology and immunotherapy. The full list of topics can be found in the meeting program.

At the moment cancer immunology and immunotherapy is a hot topic in the next generation of anti-cancer therapies. Lots of attention is given to checkpoint immunodrugs as it was proven by the prevalence of talks on this subject in the program. Indeed, this drug has great potential, but at the same time, it is not universal. About 50% of patients do not benefit from it.

What lessons have been learned from the talks:

  • Checkpoint immunotherapies are the main stream
  • Not all cancer patients would respond to immunodrug
  • Genetic landscape of a tumour and/or the patient may contribute to this, thus making beneficial to check genetics for this type of treatment
  • Immunodrugs work better in combination with conventional therapies such as chemotherapy.
  • The immune system can be tuned by a drug, but it will switch on compensatory mechanisms to balance the intervention.
  • Lots have to be studied further

 

Father of Chemotherapy and Cancer Immunology

I was giving a talk at Georg-Speyer-Haus Institute for Tumour Biology and Experimental Therapy yesterday. The aim of my visit was to establish collaboration with Prof Daniela Krause, who is the expert in bone marrow microenvironment and targeted therapies. She took me to the Institute museum that keeps the history of this place and phenomenal researchers used to work there.

This research institute was established in 1904 to support work of Paul Ehrlich, its first director and funded by the private foundation “Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus”. Paul Erlich is the Father of the chemotherapy concept originally developed to treat diseases of bacterial origin. He reasoned that there should be a chemical compound that can specifically target bacteria and stop its growth. He developed Salvarsan, the most effective drug for treatment of syphilis until penicillin came onto the market.

Paul Erlich is also known for his contribution to cancer research. He and his colleagues actively experimented on how tumour originates and spread. They also tried to understand how immune system can beat cancer applying vaccination concepts.

Paul Erlich’s Lab back then. Now it is a museum

Paul Erlich and Ilya Mechnikov were jointly awarded The Nobel Prize in Physiology or Medicine for his “work on immunity” in 1908.

 

The Nobel Prize Diploma