Yeah, our (my) blogging is sporadic. The pattern is well recognisable – more posts with success stories or accomplishments or about the key activities. It is easy to share :). Please excuse us (me) when we are off the radar, but we remember our supporters and readers. We are back on track to celebrate Childhood Cancer Awareness Month this September.
So, how did my summer go? Well, nothing to complain about. I had time to go back to the labs, pick up on the outstanding task, and take on the white coat. Indeed, it comes with some assurance as well as troubleshooting. Some days were better than others. Some experiments worked, and another was inconsistent or inconclusive.
A fancy photo, but the routine cell culture itself can be very boring.
Where did I pick it up? This research journey is one year old already. 🙂 This project is focused on validation our 3D neuroblastoma model to test novel therapeutics. We set an experiment that required different expertise and contribution from every team member. In an ideal world, it was supposed to finish in 6 months. But the reality doesn’t stop to shake you. Various components have been delayed sometimes due to unforeseen circumstances (e.g. a broken equipment or out of stock reagent) or due to the lack of manpower or miscommunication at a given time. Eventually, we put the work on hold in October 2021, when we completed ~60%. Another go to continue was taken in April 2022. No luck! Then plan B was activated, and I have been back in the labs. Despite these challenges, this time has not been lost. We developed new ideas to complement the original plan. Now, the crucial 20% has to be done and dusted within 2 weeks time before teaching starts. Wish us a luck!
After the challenge of leading the Foundation Year Medicine Cycle, I am 100% positive that I love research with all up and downs. This routine is fascinating, it is not static. One day differs from another. Research questions are flowing in non-stop…
Today marks the start of Childhood Cancer Awareness Month, which we celebrate every year to support and learn more about kids with cancer, their loving families, the doctors and caregivers who look after them and treat them, the young survivors of cancer and those kids and teens who lost their battle, and the scientists who working hard to find a way to stop childhood cancer.
Childhood cancer is an umbrella term for many other types of this disease. Every 100th cancer patient is a child. Cancer is the 2nd most common cause of death among children after accidents. When it comes to a disease, we have to acknowledge that children are not little adults. They are constantly developing. So their diseases have different ways of progressing and responding to treatment. The causes of childhood cancer, including neuroblastoma, are not known. It would be right to expect more blind alleys and failed ideas in understanding these cancers. To address these challenges, more curiosity-driven and translationally focused research is needed.
The illustration was created by Luiza Erthal
The most common childhood cancers:
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)
Despite our last blog post celebrating the regained opportunity to meet with other researchers in person and all the benefits that come with it I just had the pleasure of presenting at the first European Federation for Experimental Morphology (EFEM) Student Symposium online.
While it would have been easy for me to attend in person, as the event was hosted and organised here at RCSI, not many others would have had it quite so easy. As the name suggests, researchers from all across Europe attended. Every EFEM associated anatomical society across Europe and RCSI, as the host institution, had the opportunity to select two members to present. I was honoured to be chosen to represent RCSI. Overall, 15 different countries were represented in the student talks which made for a diverse mix that was particularly nice for the bit of organized fun at the end of the first day which encouraged networking.
Especially, because having only begun my PhD this past year I felt the category Preliminary Results and Outlook aimed at Undergrads, Masters and early-stage PhD students perfectly suited the stage of my project. This was also a brilliant way to see what other students at my level were doing in the field of anatomical research all across Europe. Having this chance to see research in progress was refreshing and uplifting contrasted with the usually more rounded later stage presentations. Having studied anatomy in my undergraduate degree I was also delighted to simply engage with more conventional anatomical research than I currently do myself.
Ronja Struck, 1Yr PhD student at the EFEM Student Symposium 2022
A wonderful opportunity to gain insights into, for example, the implicit knowledge of academia was the career development part of the conference. Talks about academia, industry and publishing offered a chance to get an inside view of those career paths at different positions within them. Especially the typical day in a research journal’s editor provided a new perspective on what is important when writing papers and will have lasting benefits for me and my scientific writing.
But by far the reason why I’ll remember this conference for the longest time is that being awarded runner up in the category Preliminary Results and Outlook reassured me that I am on the right track and that there is purpose in what I do. Despite the online format of the conference, I had the honour of receiving my prize in person, because Prof. Fabio Quondamatteo, the organiser of the event is based at RCSI.
Overall, the two days were an important step in consolidating my faith in my work and the career path that I have chosen.
Written by Ronja Struck, the IRC-CFNCRF funded PhD student
At the beginning of my career, I worked for two years in a Ukrainian company organizing international industrial conferences. So I have insider knowledge of how the conference works, and that the determining factor for the success is the active communication between the participants. And at the RCSI research day and Cork IACR conference, this component was perfect. At both events, I presented my poster and had a chance to discuss the recent advances in neuroblastoma epigenetic drug research. During RCSI Research day, I was excited to learn about the accomplishments of other undergraduate studies and was thrilled to learn that my classmate is participating in research too. He had developed an online recourse to practice cardiac auscultation, which is extremely useful for my medical studies. But professionally, I enjoyed the cancer research posters and presentations at the IACR conference and was eager to meet the researchers working on medulloblastoma, a paediatric neural cell cancer, and the research team from UCD, the neighbours of our university who worked on breast cancer. It was the most valuable opportunity to take a glimpse into other research, become inspired by the most ingenious methods, and cultivate professional knowledge and personal connections – I am so lucky I have been at RCSI Research day and the IACR conference! I have greatly enjoyed my time, and I am looking forward to (hopefully) going to the next year’s conferences again.
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 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!
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).
Looking carefully we can easily see that children are very different from adults. They have different needs, desires, likes and dislikes. Not surprisingly, the children body is also very different in their functioning and response to medical needs. Therefore, cancer in children has many different characteristics when compared to cancer in adults. Childhood cancer is different in terms of the most common types, the causes, the treatment and the course of the disease.
Firstly, childhood cancer is rare and this sometimes impairs an early diagnosis. Therefore more aggressive diseases tend to be present at the time of diagnosis. Nevertheless, there are specific types of cancer that are more common in children, which helps in the diagnosis. They are cancers affecting the blood and lymph nodes (leukaemia and lymphoma), the brain (astrocytoma), the liver and the bones (osteosarcoma). These types of cancer are less common in adults.
Another important difference between adult and childhood cancer is the leading cause of the disease. Most of the time the cause of childhood cancer is unknown, although genetic contributions related to overexpression or deletion of genes can be determined. On the other hand, adult cancers are frequently associated with alterations in the DNA (mutations) as well as lifestyle.
The treatment plays an important role in the differences between adult and childhood cancers. Usually, similar treatments are used for both adults and children, including chemotherapy, radiotherapy, surgery, transplants and immune therapy, according to the type of cancer and its stage. However, the doses and types of drugs may differ between them. The differences in the treatment go beyond the doses and encompass the mechanisms of action and possible long term toxicities of drugs. For example, the use of drugs that damage DNA can be prohibitive in children due to the increased risk of secondary cancers in the future.
In conclusion, specific types of cancer are more common in children and the cause of this disease is frequently unknown. Fortunately, children have great possibilities to survive cancers but the treatment needs to be carefully chosen and its long-term effect on the body have to be monitored for their whole life.
Written by Luiza Erthal
References
Kattner, P. et al. Compare and contrast: pediatric cancer versus adult malignancies. CancerMetastasis Rev. 38, 673–682 (2019).
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 patients1. Event-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).
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).
And the story began with a meeting of fantastic 7 at the very beginning of Dublin Mountains Way in Tallaght at 6.30 am on September 25th. The spirit, cheer, backpacks with essentials and branded tops were on, Strava was launched and we swiftly headed off.
It was quiet, dark and cheering. No one was on the streets, a few cars passed by. We took towards Bohernabreena reservoir through the sleepy estates of Tallaght, sensing the sunset. Clouds were low and the highest peaks in the Dublin Mountains including Seefingan, Corrig and the highest, Kippure were in the mist. Nevertheless, we were full of energy and hopes to see it later.
Cheat chats and jokes were here and there, we walked in small dynamic groups recalling our pre-covid life and stories that happened during the lockdown. A mix of newbies and maturating research students. We met some in person for the first time since the COVID restrictions admitting that our visual senses are extremely important to memorise a person and recognise him/her on the next occasion. We were enjoying this face-to-face communication and our team re-connection.
The first 8 km flew in a flash. We stopped for our breakfast in Dublin Mountains. The grass was wet, the sky was blue. Mountains started to draw their shape through the clouds. Yoghurts, fruits, bars immediately disappeared in our stomachs. Everyone was happy to lighten their backpack. Every little helps!
A few plasters were glued, and we continued on at a very good pace. The sky was changing with sunny spells. We travelled around Spinkeen and Killakee at their base doing up and downhills and verifying our route with the hiking app. At the 20 km mark, we stopped for lunch. Sandwiches, grapes, mandarines and sweets were shared and eaten and then polished with chocolates from the recent Nadiya’s home trip. Jellies left untouched.
At 25 km, our blisters reminded us of being humans. Our pace slowed down and we started a very mild ascent to Tibradden Mountain leaving the Pine Forest or Tibradden Wood behind. We climbed further to Fairy Castle, the highest point on the Dublin Mountains Way (537m). Throughout the entire way, Dublin showed its best views of the Phoenix Park and the Pope Cross, house roofs, Aviva Stadium, two Chimneys, Dublin Port… The scenery was fascinating and breathtaking. We saw Howth and Dun Laoghaire, Sugar Loaf… We met groups of Germans, French, Irish and many others.
At Three Rocks Mountain/Fairy Castle, we started our descent and entered Tiknock forest. This part was steep. We crossed the Gap Mountain Bike Adventure Park to reach Glencullen. Got lost at the end but just for a sec and reached the Glencullen junction at 2.30pm. It took us 8 hours with walks and stops from start to finish to complete the 30 km challenge in a day. We got tired but felt happy and satisfied.
We aimed to raise awareness of childhood cancer in general and neuroblastoma in particular as well as honour children with cancer, their parents, siblings, friends and careers, doctors and nurses, volunteers in the hospitals and researchers working to find cancer weaknesses and develop new treatments that are friendly to patients and target cancer aggressiveness.
We will count our tally in the coming days and transfer it to three wonderful charities that support childhood cancer research.
