I’ve posted extensively about Oncolytic virus trials, focused on the ongoing Neuroendocrine Cancer trial in Uppsala Sweden. I wanted to incorporate this information into a single article ready for future news, whilst at the same time updating you on further developments in the field of Oncolytic Viruses for Neuroendocrine Cancer. The excitement of the Uppsala work has dampened in recent years, not helped by the fact that one of the first patients unfortunately died. In the absence of any news, I suspect there has been no real progress and/or the funding has run out.
What exactly are Oncolytic Viruses?
Oncolytic Viruses infects and breaks down cancer cells but not normal cells. Oncolytic viruses can occur naturally or can be made in the laboratory by changing other viruses. Certain oncolytic viruses are being studied in the treatment of cancer. Some scientists say they are another type of immunotherapy whilst others say it’s too early to classify as such. The good news is that Neuroendocrine Cancer seems to figure in this work with two of these viruses apparently working on mice to date. Listed below are two active projects involving NETs, one directly and one indirectly.
The Uppsala Trial – AdVince
There has been no real update on what is happening since I posted last year. Hopefully, positive thinking indicates no news is good news. If anyone has anything more than what I’ve written or linked to in this article, please let me know. I’ll briefly describe what’s happening and then you can link to my Facebook article if you need more background.
The trial is called AdVince after Vince Hamilton who funded it. Unfortunately he died before he saw any output but his forward thinking and benevolence lives on and might hopefully help NET patients in the longer term. It’s quite a small trial and is being conducted in Uppsala University Sweden, a famous European NET Centre of Excellence and where many people from across the world attend to take advantage of PRRT availability and experience and is home to famous NET specialist Kjell Öberg, MD, PhD, a professor of endocrine oncology.
A Swedish man (Jan-Erik Jannsson) was the first to get the virus to their cancer (NETs) using a genetically modified virus.
Unfortunately, I was given the news from a source close to the trial that Jan died last year of pneumonia. I have no evidence to suggest his death is in anyway connected to the trial but I’m told he was an ill man prior to the trial commencing. I have therefore dedicated this post to him. RIP Jan.
The initial data presented by the trial indicated that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET. The last I heard from the trial is that they are trying to recruit a further 12 patients to Phase IIa (the trial document allows for up to 36).
Read more background on my Facebook post here: Click here
The trial document on Clinical Trials Website: Click here
This is an oncolytic viral therapy currently in phase III and phase Ib/II clinical trials for use against primary liver (Hepatocellular Carcinoma) and Colorectal cancers, respectively. Pexa-Vec is a weakened (or attenuated) virus that is based on a vaccine used in the eradication of smallpox. The modified virus is injected directly into the cancer tumour, to grow inside these rapidly growing cancer cells and hopefully kill them.
According to the Colorectal Clinical Trial, the aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition i.e. they are testing it in conjunction with Immunotherapy drugs (in the case of Colorectal, Durvalumab, and a combination of Durvalumab and Tremelimumab).
The Hepatocellular Carcinoma trial (Phocus) is at Phase III where the sponsors are evaluating Pexa-Vec to determine if it can slow the progression of advanced liver cancer and improve quality of life. I can other trials appearing such as this one for Colorectal Cancer and this one for any solid tumour type.
The work is a collaboration forged between University of California San Francisco (UCSF) vascular researcher Donald McDonald, MD, PhD, and researchers at San Francisco-based biotech SillaJen Biotherapeutics Inc. (formerly Jennerex Biotherapeutics, Inc.), a subsidiary of SillaJen, Inc., headquartered in Korea.
So what’s the Neuroendocrine Connection with Pexa-Vec?
As part of the research, McDonald’s lab injected it intravenously into mice genetically modified to develop pancreatic neuroendocrine cancer. They found that the virus failed to infect healthy organs or make the animals ill, but succeeded in infecting blood vessels within tumors. These initial infections caused the vessels to leak and expose the tumor cells to the virus. In these experiments, the virus managed to infect and destroy only a small proportion of tumor cells directly, the researchers found, but within five days of the initial infection, the rest of the tumor began to be killed by a powerful immune reaction. Live human trials have commenced in 2018 and the “patient 1” is a pancreatic NET patient. Read more here. Interestingly they added Keytruda (an immunotherapy) to the mix. It’s only been four months since ‘Patient 1’ (Tamara) began the trial, but a mid-treatment CT scan was said to be “promising”. I will keep this article live and bring you updates as I receive them.
Clearly it’s still early days in the Oncolytic Virus field with minimum breakthrough in terms of success on humans. In terms of the Neuroendocrine connection, it is exciting that two programmes are showing results (albeit in mice). We wait to hear from Uppsala on how the human test of AdVince is coming along. My agents are scanning the internet every day looking for any comment.
If you want to learn more about Oncolytic Viruses in general – there’s a great summary here.
“A combination of two common immunotherapy drugs shrinks rare, aggressive neuroendocrine tumors, according to new research results presented at the American Association for Cancer Research Annual Meeting 2019, held March 29-April 3 in Atlanta“. See below under section: – Nivolumab (Opdiva) and Ipilimumab (Yervoy) in Treating Patients With High Grade Neuroendocrine Carcinoma
Immunotherapy for Neuroendocrine Neoplasms
There’s a lot of Immunotherapy stuff out there! However, I also wanted to break it down and perhaps see if I can pick up the what, when, why, where and how in regards to Neuroendocrine Cancer. It’s really difficult, not least because the picture is not clear and there is no general roadmap printed, let alone one for Neuroendocrine disease. Immunotherapy for NETs was discussed at ENETS 2017 in Barcelona. The presentation that sticks out was one given by Dr Matthew Kulke, a well-known NET Specialist in Boston. My reaction to the presentation was one of ‘expectation management’ and caution i.e. it’s too soon to know if we will get any success and when we will get it. He also hinted that it’s more likely that any success will first be seen in poorly differentiated high-grade Neuroendocrine Carcinoma (NEC). Dr Jonathan Strosberg also said similar in a post here. In fact, from below you will see that grade 3 poorly differentiated is where the bulk of trial activity is (…..but read on, there is some action around plain old well differentiated NETs). You will also see that there are disappointing results so far with single agent Keytruda.
Retain hope but just be cautious with some of the hype surrounding Immunotherapy
Immunotherapy is exciting, but we also need to be aware of the risks of taking the brakes off the immune system. We have seen and heard more and more stories about people with grim cancer diagnoses who became cancer-free after treatment with immunotherapy. This offers hope to those with cancer, but we need to be cautious when discussing immunotherapy. This treatment method is still new, and the cancer community is still learning about how it affects the body. An unfettered immune system may end up attacking healthy, functioning parts of a person’s body, causing unpredictable side effects that may be life-threatening EVEN if not treated early.
For Neuroendocrine Neoplasms, only Neuroendocrine Carcinoma of the skin (Merkel Cell Carcinoma) has an approved drug (see below). Anything else is currently an experimental scenario (clinical trial). Before launching into what is out for with an interest in NET and NEC, it’s worth pointing out that Immunotherapy is not for everyone, does not work for everyone, and has side effects for everyone.
Worth also noting that NANETS 2018 reported limited use of Keytruda (see below) as a single agent to treat high grade Neuroendocrine Neoplasms.
Let’s start with Pembrolizumab (Keytruda)?
‘Pembrolizumab’ is more famously known as ‘Keytruda‘. This drug crops up everywhere and it has connections to many different cancers. Before I talk about this trial called PLANET, it’s very useful to take a quick look at the history of Keytruda which was only really made famous after former US President Jimmy Carter was treated with it for metastatic melanoma. There was a lot of media hype surrounding what made his treatment successful as he was also given radiation for his brain tumours and his large liver tumour was removed by surgery. However, putting the hype and conjecture to one side, Keytruda’s CV is pretty impressive:
Pembrolizumab (Keytruda) is currently approved to treat:
Hodgkin lymphoma in adults and children. It is used in patients whose disease is refractory (does not respond to treatment) or has relapsed after at least three other types of treatment.
Melanoma that cannot be removed by surgery or that has metastasized (spread to other parts of the body).
In patients whose cancer has the PD-L1 protein and got worse during or after treatment with platinum chemotherapy. Patients whose cancer has EGFR or ALK gene mutations should receive Pembrolizumab only if their disease got worse after treatment with an FDA-approved therapy for these mutations.
in combination with Pemetrexed and Platinum as first-line treatment of patients with metastatic, non-squamous non-small cell lung cancer.
Urothelial carcinoma (a type of bladder cancer) that is locally advanced or has metastasized. It is used in patients who cannot be treated with cisplatin or whose disease got worse during or after platinum chemotherapy.
Microsatellite instability-high (MSI-H) cancer that is metastatic and cannot be removed by surgery. It is used in adults and children for:
Solid tumors that have gotten worse after other treatment or that cannot be treated with other therapies.
MSI-H cancer has certain genetic mutations and may not respond to some types of treatment.
The most recent approval in May 2017 MSI-H disease is a very interesting development as it’s the US FDA’s very first approval on a tissue/site agnostic basis. You can read about this approval here. Cancers of the breast, prostate, thyroid, bladder, colon, rectum and endometrium are just some of the cancers that have been found to have these biomarkers and would be new possible targets for Keytruda. There’s a great article which explains this approval in an easy way – click here to read.
Other approvals are anticipated.
So what about Neuroendocrine Neoplasms?
FDA granted accelerated approval to Avelumab (BAVENCIO) for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma (MCC). MCC is a Neuroendocrine Carcinoma of the skin. Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. This is the first FDA-approved product to treat this type of cancer – CLICK HERE for more information.
In Aug 2018, the FDA granted Nivolumab (OPDIVO) accelerated approval for third-line treatment of metastatic small cell lung cancer (a type of Neuroendocrine Carcinoma. Read more – click here.
On March 18, 2019, the FDA approved Atezolizumab (TECENTRIQ) in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).
This trial is interesting. Nivolumab (Opdiva) and Ipilimumab (Yervoy) in Treating Patients With High Grade Neuroendocrine Carcinoma It’s a multiple cancer setup and includes several of the less common NET/NEC types including ‘Lung Carcinoid’, ‘Anal NEC’, ‘Gastic NEC’, ‘Pancreatic NEC’ ‘Esophageal NEC. Interesting because this is the drug combo that NEC patient Danielle Tindle has moved onto after Keytruda didn’t really work in the medium to long-term (see the Danielle Tindle story below). Looking at the list in the trial document, I’m thinking they might mean high-grade Lung Neuroendocrine rather than ‘carcinoid’. I could be wrong. It’s currently recruiting.
Update from 2019 AACR Annual Meeting.
The immune checkpoint inhibitor combination of nivolumab (Opdivo) and ipilimumab (Yervoy) induced a greater than 40% response rate and was well tolerated in patients with high-grade neuroendocrine carcinoma, according to findings from the phase II DART trial presented at the 2019 AACR Annual Meeting.
“DART is the first NCI-funded rare tumor immunotherapy basket study which we think is unique in its design scale,” lead author Sandip Patel MD, an associate professor of medicine at the University of California San Diego School of Medicine, said in a press briefing at the meeting. “We’re studying over 37 rare tumor types [using the] combination of ipilimumab plus nivolumab. The neuroendocrine cohort, the nonpancreatic cohort, had promising signs of benefit—[particularly] in patients with high-grade neuroendocrine carcinoma—independent to primary site,” added Patel.
I also have some evidence of the use of Pembrolizumab (Keytruda) by an Australian high-grade thymus patient – I posted something here (Danielle Tindle)
Merkel Cell Carcinoma – a type of Neuroendocrine skin carcinoma is benefiting from Immunotherapy. Worth noting that this type of Neuroendocrine Carcinoma already has an FDA approved immunotherapy drug (Avelumab (Bavencio)) with another pending (Keytruda)
PDR001 (Spartalizamab) – click here.
UPDATE from NANETS 2018. “A preliminary trial of checkpoint blockade for neuroendocrine tumors (NETs) produced little evidence of activity, according to data reported here. Only one of 21 patients with high-grade NETs responded to treatment with pembrolizumab (Keytruda). Three others had stable disease. The trial had an objective response threshold of 5% as the definition of clinically interesting, as reported at the North American Neuroendocrine Tumor Society annual symposium. “Pembrolizumab, though generally well tolerated, showed limited activity as a single agent in high-grade neuroendocrine neoplasms (NENs) in this study,” Arvind Dasari, MD, of MD Anderson Cancer Center in Houston, and colleagues concluded.” More info.
Update from Gastrointestinal Tumor symposium 2019. “Disappointing results for single agent pembrolizumab (Keytruda) in well differentiated NET. Response Rate 3.7%. Not a viable option. Listen to Dr Jonathan Strosberg describe the poor results. Click here.
This is an interesting trial sponsored by Novartis (of Octreotide fame). PDR001 (anti-PD-1) is an investigational immunotherapy being developed by Novartis to treat both solid tumors and lymphomas (cancers of the blood). It is currently being trialled on many cancers including Neuroendocrine Neoplasms both well and poorly differentiated. Click here: Clinical Trial SPARTALIZUMAB – Immunotherapy for Neuroendocrine Neoplasms (PDR001)
NET Research Foundation
Please also see the wonderful work done by NET Research Foundation who are using their funds to explore the use of Immunotherapy in NETs – check out their update by clicking here.
But what about just plain old well differentiated low or moderate grade NETs?
I found the following:
Pembrolizumab (Keytruda) in combination with Lanreotide
According to the trial documentation, it’s for patients with non-resectable, recurrent, or metastatic well or moderately (sic) differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). i.e. most of us. It is recruiting. You can read about the PLANET trial by clicking here. Make sure you fully check the inclusion and exclusion criteria. Please note the incorrect reference to ‘moderately differentiated’ – this is no longer used in the grading classification for Neuroendocrine Neoplasms.
Study of Pembrolizumab in Participants With Advanced Solid Tumors (MK-3475-028/KEYNOTE-28) – NCT03054806 and another called ‘A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects With Advanced Solid Tumors’ (KEYNOTE 158) NCT02628067
From Gastrointestinal Tumor symposium 2019. “Disappointing results for single agent pembrolizumab in Well Differentiated NET. Response Rate 3.7%. Not a viable option. Listen to Dr Jonathan Strosberg describe the poor results. Click here.
Study for the Evaluation of Pembrorolizumab (MK-3475) in Patients with Rare Tumors (Experimental: Paraganglioma-Pheochromocytoma Group)
It is not known if this part of the trial is affected by the results above in Keynote-28. This study is recruiting at MD Andersen Houston Texas. Read more here.
PDR001 (Spartalizamab) -a Novartis drug – read about this trial click here.
Atezolizumab and Bevacizumab in Solid Tumors
In 2016, US FDA approved Atezolizumab (TECENTRIQ) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC). Bevacizumab (also known as AVISTAN) is a well known drug already used to treat many cancers. Avastin is not actually Immunotherapy but is a tumor-starving (anti-angiogenic) therapy, i.e. its purpose is to prevent the growth of new blood vessels …. ergo this is a combo treatment using an Immunotherapy drug and an anti-angiogenic drug.
Well differentiated Neuroendocrine tumors, Grade 1 or grade 2 according to reviewing pathologist
Progressive disease over the preceding 12 months
Any number of prior therapies
Patients using a somatostatin analogue for symptom control must be on stable doses for 56 days prior to enrolment.
According to the trial documenation, there are two ‘baskets’ of types: Pancreatic NET (pNET) and “extrapancreatic” (i.e. beyond or not in the pancreas) including typical or atypical Lung NETs. Merkel Cell Carcinoma (a type of Neuroendocrine Carcinoma of the skin) is also included in the trial. You can read about this trial by clicking here. Make sure you fully check the inclusion and exclusion criteria. Again, within the trial documentation, please note the incorrect reference to ‘moderately differentiated’ – this is no longer used in the grading classification for Neuroendocrine Neoplasms.
By the way, what exactly does Immunotherapy do?
For those still wondering what cancer immunotherapy actually is, this is the most basic description I could find!
Immunotherapy – Hype or Hope?
I mentioned above that there was a lot of hype surrounding Keytruda and other immunotherapy treatments. You may therefore enjoy this CNN article about the hype and hope aspect, it was given considerable sharing at ASCO17 – read the article by clicking here
If you’re on an Immunotherapy trial not listed here, please let me now so I can update the post. Thanks in advance.
As I have a 2 year old post about Danielle, I wanted to preface it with this message.
It is with great sadness that I let you know Danielle Tindle passed away at the end of August 2017 after a prolonged battle with Neuroendocrine Carcinoma. She had been fighting cancer in one form or another for 12 years and became passionate in campaigning for more attention for young cancer patients. I’ve been following her story for almost 2 years and she has really inspired me. The title of this article is based on the title of a TV programme about her and her campaign to gain access to new drugs. I had chatted with Danielle online about some of the story below and I hope I’ve interpreted it correctly. RIP Danielle.
I first wrote about Danielle Tindle in Oct 2015 as I was really inspired by her story. Some of you will know that I have a lot of time for inspiring patient stories such as this one. There is no better form of advocacy and awareness than a human being talking about it in front of a camera or microphone. I truly believe these should be at the forefront of international and national campaigns.
Danielle has appeared many times in the national newspapers and TV in Australia. A young person who had gone through gruelling treatments – several chemos and stem cell treatment for get rid of Hodgkin’s Lymphoma. One of her chemo treatments resulted in permanent loss of hair (severe Alopecia) – listen to her very inspirational video by clicking here. She talks about this aspect of her treatment plus many other things. A quote I love is her saying “to be treated like I’m unwell makes me very angry”.
Just when she thought her life was back and near the end of a PhD, they found a Neuroendocrine Tumour in her neck near the larynx which was inoperable and chemo was found to be ineffective. Despite this, she battled on. Her father, a scientist, had coincidentally been involved in the research of an experimental immunotherapy drug, which was at the time being used for Melanoma. Pembrozilumab (KEYTRUDA) has since been approved for a number of cancers including Melanoma, Hodgkin’s Lymphoma, metastatic nonsquamous non-small cell lung cancer (NSCLC); and very recently for advanced or metastatic urothelial carcinoma.
Danielle’s story had also highlighted a growing problem which appears to be causing concern in many countries – the price of drugs which is then compounded by health system processes. How crazy was this ……. Danielle initially wanted to take Pembrozilumab (KEYTRUDA) (made famous by former US President Jimmy Carter) on an experimental basis (……it is not approved for any type of Neuroendocrine Cancer). It would only cost AUS$6 AUS if she was a Melanoma patient but because she has Neuroendocrine Cancer, it cost AUS$5000 a shot for the treatment she needs. You can view the 30-minute ABC ‘Australian Story’ by clicking here
Danielle has confirmed to me that she did eventually try Pembrozilumab (KEYTRUDA) but she was then moved onto a combination of Nivolumab (OPDIVO) and Ipilumumab (YERVOY), also immunotherapy drugs. In fact, the Nivolumab and Ipipumumab did initially make progress with some tumour size reduction – click here. But …….
Unfortunately, from an update gleaned from her ‘gofundme‘ site (Apr 2017), it would appear progress with Nivolumab and Ipipumumab halted, things started to grow and the treatment was stopped. Danielle was then put into palliative care for pain relief. She has had a number of emergency surgeries, including a feeding tube directly to her stomach to eat, and a tracheostomy (a tube that goes into your neck so that you can breathe).
Then a new breakthrough when her oncologist advised that the treatment protocol for immunotherapy had changed and that there may be benefit in continuing to treat her. However, the financial constraints still apply. Despite, Danielle having paid $123,000 for the immunotherapy so far, the drug company has AGAIN denied compassionate access to the treatment.
When I wrote the original blog, I attached a 5-minute video which I personally found very inspiring. She talks eloquently, confidently and she maintains her composure emotionally. She was a brave lady and I’m not sure I could have contained my emotions for the full 5 minutes of the video clip. You can view the video clip here: Click here to view. (Please note this video was recorded before the immunotherapy treatment).
Thanks for reading
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