Will there ever be one cure for cancer?

TL;DR – probably not.

Cancer is a disease which will have an impact on most people throughout their lifetimes, and there are few things that can bring people to agreement more than wanting a cure for this disease. But despite countless years of financial investments and researchers who dedicate their careers to cancer, we still don’t have a “cure”, and it can be difficult for non-scientists to fathom why.

One key concept to understand here is that cancer is not a single disease, does not have a single cause, and therefore cannot have a single cure. The differences between neuroblastoma and breast cancer are vast. And similarly, between patients with the same cancer type (e.g. two patients with breast cancer), the differences can be equally as big. Let’s for a minute, take an analogy of a large business company. (Disclaimer, I have never studied business in my life, so please humour me). The company is run by a CEO and board of directors and has many different departments with managers and teams of workers with specific roles. Suddenly, business is declining, and the company is not sure why. For one business, maybe this is down to someone in the Communications team spreading misinformation. For another, maybe a mistake has been made in the Finance team, which has had a knock-on effect on the other departments. Maybe Human Resources have not been properly reprimanding staff who have broken protocol. With hundreds of staff working in the company, it can be hard to pinpoint exactly where the problem has arisen, which has negatively impacted the company as a whole.

Standard business hierarchy, created with BioRender.com

Human cells aren’t so different to a company. They have a central “nucleus” tasked with controlling the functioning of the cell as a whole (Board of Directors/Management). They have proteins which relay messages inside the cell, as well as outside with other surrounding cells (Communications). They have proteins which are responsible for detecting when something goes wrong, to correct or destroy whatever is acting out of place (Human Resources). Issues within any of the “departments” in a human cell can potentially lead to cancer, and just like our business model, it can be hard to trace where the problem arose, and it is often different between two cancers.

Cell signalling networks, or the “business departments” within a cell, from Reactome.org

For decades cancer was treated with chemotherapy, famous for attacking the good healthy cells as well as the bad. The research focus has now shifted towards more targeted therapies. An example of this is Herceptin therapy for breast cancer. This therapy targets a specific protein called HER2. HER2 is a team within the Communications department in breast cells. It receives communications from outside the cell, which tells the cell it’s time to grow, and relays this message to the Nucleus, which instructs proteins involved in cell growth to start this process. However, in some breast cancers, there are too many members in the HER2 team, all relaying this message to the Nucleus, resulting in too much cell growth. Herceptin is a drug which specifically targets HER2 and prevents it from relaying this message, effectively preventing the cancer cells from growing. While this can be very efficient at preventing tumour growth in HER2+ breast cancer, HER2 is not the culprit in all breast cancers. It is estimated that only 1 in 5 breast cancers have too many members in the HER2 team (Irish Cancer Society), and so targeting this will be inefficient in treating 4 out of 5 breast cancers. Meanwhile, cells of other cancers, such as liver or thyroid cancer, may not even have a HER2 team.

Hopefully, it is becoming clear why one “cure” will likely never be a reality. All cancers are different, all have different causes, and different employees breaking protocol. So, a one-size-fits-all approach simply can’t work. Instead, we need to focus on finding common company malpractices for each cancer, such as HER2 in breast cancer, generate a repertoire of different targeted treatment options depending on the various causes of cancer, and treat each patient as an individual investigation to determine what employee/protein is acting out of line to cause their cancer, so we can specifically reprimand them.

Written by Catherine Murphy

Paris…Paris…

I’m Ellen, and I am a 3rd year PhD student in the Cancer Bioengineering Group. Last week I attended and presented at my first international conference, ISCT (International Society for Cell & Gene Therapy), in Paris. I spent five days in Paris with three of them at the conference where scientists, researchers and pharma professionals came from far and wide. There was a strong focus on collaboration between industry teams and academics, and it gave me a lot to think about when it comes to my own PhD and career journey as a whole.

As a soon-to-be final-year student, the next step in my career has been on my mind. Starting out, I was very sure I wanted to progress within academia and follow the “traditional” researcher route. Industry always seemed so far removed from the basic sciences, and specifically biology research roles are hard to come by in Ireland. Having the opportunity to travel to Paris and meet with such a wide range of professionals really opened my eyes to the possibility of a career in the industry. It was reassuring to see that even after leaving academia, there is a cross-over and lots of collaboration. Industry or academia? The fork in the road when it comes to this career choice is becoming lesser and lesser.

While I was in Paris, I had a lot of time to ponder the fantastic science and research that I discussed at the talks (Did you know? One adult human heart produces enough energy in one lifetime to power an 18-wheeler to the moon and back). Additionally, I could also see first-hand that the positive aspects that we associate with academia (presenting research, freedom of research topics and the conference wine receptions, of course) are also readily available as a non-academic based scientist. In fact, there is a career that has the “goodness of both”. So many academics discussed start-ups and spin-out companies developed off the back of their academic research, and there were even talks that discussed the how, what, when and where of transitioning between the two settings.

I’m so grateful that I could attend this conference. I presented my research (a project very much blended between academia and industry), got to chat to like-minded people and came home with a wealth of new knowledge. This knowledge will not only enrich my PhD project but will stand for me as my career moves from student to fully-fledged scientist. The topic of post-PhD job hunting often comes with a knot in the stomach, but seeing the exciting opportunities that are available out there has me much more excited than stressed about this next step. And now to finish this PhD so that I can take that next step 🙂

My trip became possible thanks to the Company of Biologist travel grant and support from the RCSI Department of Anatomy and Regenerative Medicine.

Written by Ellen King

A February Full of Conferences

For a short month, we really made the most of February in the Cancer Bioengineering Group. We attended not one, but two conferences both outside of Dublin, with presentations from every member of the group and more great memories made.

At the end of 2022, I was lucky enough to be sent on a 3-month research secondment to the Institute for Bioengineering of Catalonia (IBEC) in Barcelona, so I was delighted to return in February for the Transdisciplinary Approaches in Neuroblastoma Therapy symposium. I got to present my work from my secondment in “Flash-poster” style, alongside other group members Ciara, Lin & Alysia. Ellen and Ronja also did a great job presenting a more extended cut of their research, and we got to see team lead Olga give a round-up of our group’s work as a whole.

Barcelona, Spain, February 2023

Outside of the conference schedule, I was tasked with the role of Tour Guide because of my familiarity with the beautiful city of Barcelona. I led a group of 20+ researchers to a small bar in the Gothic Quarter for some well-deserved refreshments after a day of conferencing, brought my team to my favourite tapas restaurant for lunch (I still dream of the croquetas) and went on a lovely walk up Montjuic Hill to take in the views of Barcelona and reminisce on the 3 months I had spent there.

It felt as though the Ryanair flight had just touched down in Dublin when we started preparing for another conference – the Irish Association for Cancer Research (IACR) meeting, taking place in Athlone. With great memories from IACR 2022 in Cork, I prepared for the conference with great excitement – looking forward to both interesting science talks, and good craic with the gang of RCSI researchers attending the conference. I had a poster presentation for this, again focussing on the work I carried out on secondment in IBEC as well as some work at home in RCSI. I enjoyed my chats with the poster judges who gave some good insights on the work. Ellen and Lin had oral presentations at the conference so again I got to resume my role as the group Twitter mom, taking pictures and drafting tweets while the girls showcased their great research.

IACR Meeting 2023, Athlone, Ireland

Each day when the conference was drawn to a close we set our sights on having a bit of fun with the other attendees. We enjoyed a pint of Guinness and some Trad music in the oldest bar in Ireland – Sean’s bar (they had the certificate to prove this). We made friends from outside RCSI including researchers from Queens University Belfast and Sales Representatives from various lab supply companies, had a good dance in the residents’ bar of our hotel and took over the dancefloor of a small local club.  The gala dinner was lovely as always, and I’ll forever have fond memories of my lab group playing “Heads Up” to entertain ourselves in between courses. Finally, a highlight for me was being given a Highly Commended Poster Award at the dinner, such a nice acknowledgement to receive for my work and a lovely way to wrap up the last conference of my PhD.

Written by Catherine Murphy

IACR Meeting 2022: 2 years + a pandemic in between

It was February 2020, just before one of the biggest global pandemics struck, that I attended the IACR as a research assistant. It was my first official conference and it is safe to say ‘Imposter Syndrome’ was my main feeling going down to Galway on the train. Fast forward 2 years and my feelings travelling to IACR 2022 in Cork could not be more different. It is amazing what starting a PhD during a pandemic can do for your confidence and skills as a researcher – a sink or swim moment if there was ever one. My first IACR in Galway was one to remember surrounded by like-minded scientists, all brimming with new ideas and exciting discoveries. As such, I had high hopes for IACR 2022. And it did not disappoint.

Ellen King, PhD student at the IACR Meeting 2022

My PhD project focuses on the development of a vaccine to treat neuroblastoma so I was very excited to hear talks from some of the leading experts in vaccine research, both in industry and academia. I gained so much from hearing these experts discuss their research but also discussing other important topics like career progression and how to keep a work/life balance in research. It was refreshing to hear that as scientists we don’t have to (and shouldn’t) work ourselves to the bone 24/7 to be successful. As a young scientist planning to continue into academic research, this left a lasting impression on me. To top off what was already a hugely beneficial conference for me, my poster was shortlisted for a prize. I was shocked, delighted and excited all-in-one. Starting my PhD during a pandemic was not without challenges. Delays in deliveries, delays getting trained on equipment and multiple lockdowns led to what felt like (for me) quite a disjointed start. For my research to be shortlisted by experts was, to be honest, a relief. To know that my work stood out was extremely important to me and that all the hard work does pay off. When my name was called out at the Gala dinner as a Poster Prize Winner, all the doubts that I had (doubts that we all have as scientists) disappeared. I felt very proud and very grateful that my research was recognised at that level. There is no doubt that in-person conferences give a huge boost to young researchers, and I really look forward to presenting my work at the next IACR meeting.

Written by Ellen King

First Research Meeting For A Medical 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.

Written by Nadiya Bayeva

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).