Novel Immunotherapy Combination Shows Promise in Some with Resistant Metastatic Colon Cancer

MedicalResearch.com Interview with:

Dr James Kuo, MBBS Medical oncologist and Deputy Medical Director Scientia Clinical Research Sydney, Australia 

Dr. Kuo

Dr James Kuo, MBBS
Medical oncologist and Deputy Medical Director
Scientia Clinical Research
Sydney, Australia

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Immune checkpoint inhibitors (ICI) that have seen success in the treatment of patients with various tumour types have not been as effective in patients with metastatic pancreatic cancer and therefore immune-therapeutic agents of novel mechanism of action, in particular in combination with existing ICI, need to be investigated.

This study set out to test the safety and efficacy of pixatimod, a novel immunomodulatory agent, in combination with nivolumab, firstly in the dose escalation cohorts in patients with any solid tumour for the maximal tolerable dose, and then using this dose to further treat an expansion cohort of patients with pancreatic cancer. Altogether 16 patients had received the combination and in 10 patients in whom treatment response was evaluable, 4 patients experienced a clinical benefit and continued treatment in the trial, with 1 patient having a significant partial response now treated for 48 weeks. Interestingly, all these 4 patients had metastatic colorectal cancer. Side effect profile has been consistent with other immunotherapeutic agent combination and in the patients who had clinical benefit, no treatment related side effects were observed.  Continue reading

Heavy Alcohol Use Early in Life Linked to Aggressive Prostate Cancer

MedicalResearch.com Interview with:

Emma H. Allott, PhD Research Assistant Professor of Nutrition UNC GILLINGS SCHOOL OF GLOBAL PUBLIC HEALTH  University of North Carolina, Chapel Hill 

Dr. Emma Allott

Emma H. Allott, PhD
Research Assistant Professor of Nutrition
UNC GILLINGS SCHOOL OF GLOBAL PUBLIC HEALTH
University of North Carolina, Chapel Hill 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Prostate cancer development may span decades. In addition, the prostate grows rapidly during puberty and therefore may be particularly susceptible to dietary or lifestyle factors during this time.

Our study found that heavier alcohol intake earlier in life, as well as higher cumulative alcohol intake across the lifespan, was associated with an increased odds of being diagnosed with an aggressive (clinically significant) prostate cancer in later life. However, current alcohol intake at the time of prostate cancer diagnosis was unrelated to tumor aggressiveness.

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Kidney Cancer: Biomarker Linked to Detection and Progression

MedicalResearch.com Interview with:

Dr. David Muller, PhD  Faculty of Medicine, School of Public Health Research Fellow in Epidemiology and Biostatistics Imperial College London

Dr. Muller

Dr. David C. Muller PhD
Faculty of Medicine, School of Public Health
Research Fellow in Epidemiology and Biostatistics
Imperial College, London

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Our colleagues in the U.S. have been working on KIM-1 for years, particularly in the context of chronic kidney disease. Recently they found that KIM-1 is also elevated at the time of diagnosis of kidney cancer.

We wanted to see if KIM-1 concentrations could predict the chances of a future diagnosis of kidney cancer. We found that KIM-1 was a strong predictor of being diagnosis with kidney cancer in the next 5 years. We also found that higher pre-diagnostic KIM-1 was associated with worse survival after diagnosis.  Continue reading

Granzyme B Probe Plus PET Scanning Helps Determine Response To Immunotherapy

MedicalResearch.com Interview with:

Ben Larimer, PhD research fellow in lab of Umar Mahmood, MD, PhD Massachusetts General Hospital Professor, Radiology, Harvard Medical School

Dr. Ben Larimer

Ben Larimer, PhD research fellow in lab of
Umar Mahmood, MD, PhD

Massachusetts General Hospital
Professor, Radiology, Harvard Medical School

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:
Although immunotherapies such as checkpoint inhibitors have revolutionized cancer treatment, unfortunately they only work in a minority of patients. This means that most people who are put on a checkpoint inhibitor will not benefit but still have the increased risk of side effects. They also lose time they could have spent on other therapies. The ability to differentiate early in the course of treatment patients who are likely to benefit from immunotherapy from those who will not greatly improves individual patient care and helps accelerate the development of new therapies.

The main purpose of our study was to find a way to separate immunotherapy responders from non-responders at the earliest time point possible, and develop an imaging probe that would allow us to distinguish this non-invasively.

Granzyme B is a protein that immune cells use to actually kill their target. They keep it locked up in special compartments until they get the right signal to kill, after which they release it along with another protein called perforin that allows it to go inside of tumor cells and kill them. We designed a probe that only binds to granzyme B after it is released from immune cells, so that we could directly measure immune cell killing. We then attached it to a radioactive atom that quickly decays, so we could use PET scanning to noninvasively image the entire body to see where immune cells were actively releasing tumor-killing granzyme B.

We took genetically identical mice and gave them identical cancer and then treated every mouse with checkpoint inhibitors, which we knew would result in roughly half of the mice responding, but we wouldn’t know which ones until their tumors began to shrink. A little over a week after giving therapy to the mice, and before any of the tumors started to shrink, we injected our imaging probe and performed PET scans. When we looked at the mice by PET imaging, they fell into two groups. One group had high PET uptake, meaning high levels of granzyme B in the tumors, the other group had low levels of PET signal in the tumors. When we then followed out the two groups, all of the mice with high granzyme B PET uptake ended up responding to the therapy and their tumors subsequently disappeared, whereas those with low uptake had their tumors continue to grow.

We were very excited about this and so we expanded our collaboration with co-authors Keith Flaherty and Genevieve Boland to get patient samples from patients who were on checkpoint inhibitor therapy to see if the same pattern held true in humans. When we looked at the human melanoma tumor samples we saw the same pattern, high secreted granzyme levels in responders and much lower levels in non-responders.

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President of AACR Discusses Sixth Annual Cancer Progress Report

MedicalResearch.com Interview with:

Nancy Davidson, MD President of the American Association for Cancer Research (AACR) and Director, University of Pittsburgh Cancer Institute

Dr. Nancy Davidson

Nancy Davidson, MD
President of the American Association for Cancer Research (AACR) and
Director,  Cancer Institute
University of Pittsburgh

Dr. Davidson discusses the 2016 AACR Cancer Progress Report. “The report serves as an educational document for both Congress and the public, alike. The report is a call to action, designed to urge Congress and the American public to stand firm in their commitment to the conquest of cancer”.

MedicalResearch.com: What is the background and goals for this report?

Dr. Davidson:

  • This is the sixth edition of our annual Cancer Progress Report.
  •  The annual report is the cornerstone of the AACR’s educational and advocacy efforts:
  • The report outlines efforts to increase public and Congressional understanding of cancer and the importance of cancer research to public health and
  • Efforts to advocate for increased federal funding for the NIH, NCI, FDA, and other federal agencies that are vital for fueling progress against cancer
  • The first report was written in 2011, the year that marked the 40th anniversary of the signing of the National Cancer Act of 1971, to commemorate the advances in cancer research that had been made to date and to paint a picture of where the science was leading us.

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RANK signaling-blockade reduces breast cancer recurrence by inducing tumor cell differentiation

MedicalResearch.com Interview with:

Eva Gonzalez Suarez, PhD Group Leader Transformation and Metastasis lab. Cancer Epigenetics and Biology Program-PEBC Institut d'Investigació Biomédica de Bellvitge-IDIBELL Hospital Duran i Reynals Avinguda Gran Via de l'Hospitalet, L'Hospitalet de Llobregat-Barcelona-Spain

Dr. Eva Gonzalez Suarez

Eva Gonzalez Suarez, PhD
Group Leader Transformation and Metastasis lab.
Cancer Epigenetics and Biology Program-PEBC
Institut d’Investigació Biomédica de Bellvitge-IDIBELL
Hospital Duran i Reynals Avinguda Gran Via de l’Hospitalet,
L’Hospitalet de Llobregat-Barcelona-Spain

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Thousands of cancer patients worldwide are taking RANKL inhibitors for the management of bone metastasis, based on the key role of RANKL and its receptor, RANK, driving osteoclastogenesis. RANK signaling pathway acts as a paracrine mediator of progesterone in mouse and human mammary epithelium. RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remained unknown.

Complementary genetic and pharmacological approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation and enhances sensitivity to chemotherapy in mouse models that closely resemble the clinical disease. Mechanistically, genome wide expression analyses showed that anti-RANKL therapy promotes differentiation of tumor cells into milk-producing cells, as observed during pregnancy.

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Math Algorithm Helps Predict Recurrence of Prostate Cancer


MedicalResearch.com Interview with:  

Ilaria Stura PhD

Università degli Studi di Torino
Turin, Piedmont, Italy


MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Man has always tried to predict the future, especially to prevent catastrophes, diseases and death. In this case, we want to prevent the ‘personal catastrophe’, i.e. the spread of the disease (recurrence of prostate cancer) in the patient. Our work therefore belongs to the so-called ‘personalized medicine’, a very important and innovative clinical approach.

In particular this study may potentially improve the quality of life of the patients and help the clinicians, since it could give valuable information to the urologist, for example reporting that the growth velocity of the tumor is increasing and that a relapse is expected within few months. With this information, the clinician could chose the best therapy for the patient (e.g. hormone or radio therapy) in order to stop the spread of the disease or, conversely, the use of drugs can be delayed if not necessary.

Obviously clinicians already try to do this, based on their experience, but our method provides further confidence in their ‘investigation’ work, since the algorithm is validated on data coming from a database much larger than his/her personal experience.

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Changing Delivery Method Reduces Pain of Neuroblastoma Treatment

Prof. Dr. Holger Lode Clinical Immunology, Pediatrics University of Greifswald, GreifswaldMedicalResearch.com Interview with:
Prof. Dr. Holger Lode

Clinical Immunology, Pediatrics
University of Greifswald, Greifswald

Medical Research: What is the background for this study?

Response: Neuroblastoma is a cancer in childhood with one of the highest death rates.  Standard treatment is already very intensive. It includes chemotherapy, surgery, radiation, high dose chemotherapy followed by autologous stem cell transplantation. However, the progress made in improving survival rates is still poor.

The use of an immune-modulatory treatment with a neuroblastoma specific monoclonal antibody ch14.18 (100 mg/m2 /cycle) in combination with cytokines and 13cis retinoic acid (13 cis RA) has shown benefit for patients with this disease [1].  This antibody targets ganglioside GD2 abundantly expressed on neuroblastoma with limited to no expression on healthy tissue. Low expression of GD2 on pain fibers is associated with an on-target side effect of the treatment, which is the induction of neuropathic pain. Approval of ch14.18 (dinutuximab) for the treatment of children with neuroblastoma has been provided by FDA.

In Europe, ch14.18 was not available for a long time. There were several reasons why the antibody in the US could not be given to children in Europe. Therefore a new development of this side of the Atlantic was initiated following the remanufacturing of the antibody in CHO cells [2] (dinutuximab beta) and was made available within clinical trials of the SIOPEN group. The SIOPEN group is a network of leading European pediatric oncology centers to improve outcome for children with neuroblastoma (http://www.siopen.org), similar to the COG (children`s oncology group in the USA; https://www.childrensoncologygroup.org).

Following the recloning procedure, ch14.18/CHO was first evaluated for safety in a Phase I study [3], which confirmed the tolerability and showed activity at a dosing regimen of 20 mg/m2 given by 8 hour infusions on 5 consecutive days. Dinutuximab beta is further developed by Apeiron Biologics.

The current way to apply 100 mg /m2 / cycle is by 4 short term infusions of 25 mg/m2/day each over 8 hrs on 4 consecutive days. The entire treatment consists of 5 cycles. The drawback is that STI is associated with a high amount of intravenous morphine required to make this treatment tolerable for patients. Also the rate of inflammatory side effects observed is substantial.

Clinical observation indicates that if patients treated by STI suffer from pain despite analgesic treatments, a decrease in speed of antibody infusion improves this on target toxicity. Therefore, we hypothesized that significant prolongation of the time of antibody infusion will improve tolerability of that treatment, but at the same time maintains clinical activity and efficacy in high risk neuroblastoma patients.

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