Hi, I'm Dr Pete Smith, immunologist at St George's University with a special interest in immunotherapy as a treatment for cancer. AMA!

Hi Pete! In 2020, my mum (in her early 60s) was told by doctors that a previously treated melanoma had spread through her body. This was at the height of the pandemic, where patients were unfortunately waiting longer than usual for treatment.

My mum was incredibly active - she ran daily and cycled 10 miles to and from work each day but by mid 2020 she was barely able to get around - some part of the cancer had created fluid which pressed on her stomach/gut, and she could hardly walk. Eventually though, she was given immunotherapy and nearly instantly she experienced a massive improvement in her quality of life - she was able to run and cycle again, and most importantly, she was happy, for a good six months or so.

Unfortunately towards the end of 2020, her health started rapidly declining again, and she passed away in early 2021. It was an immense loss, which I still feel today, but I’ll always be grateful for the six months of so of extra time that I got with her, where she was happy and enthusiastic about life. So thank you for the work you do on immunotherapy, because it was single-handedly responsible for giving me that time.

Regarding my questions, I have two:

• Is my mum’s experience (rapid improvement in health/quality of life, followed by a sharp downturn) a common experience with immunotherapy? Is it that patients bodies get used to the treatment eventually? And if so, is this something that folks like you are actively looking to solve?

• Is there somewhere I can donate to that will help fund immunotherapy research and development?

Thank you again for your work, really.

Thanks for your comment. Sorry for the loss of your mum.

Generally for Melanoma some patients 'respond' to treatment and some currently do not (this is referred to as primary resistance). This could be for a number of reasons. For those who respond, some do so for many years without the re-emergence of tumours but some patients develop what's referred to as acquired resistance. There are a few reasons for this acquired resistance but ultimately the tumour evolves to escape or inhibit the immune response generated through immunotherapy. This is being intensively studied in order to improve both the number of people who can benefit and prevent the onset of resistance. As an immunologist studying cancer immunotherapy I'm pleased for you that it was at least partially helpful for your mum and am optimistic and determined that improvements to immunotherapy will continue to be made in the years ahead.

The ICVI is a charity that funds my research, and other immunologists, specifically in order to improve immunotherapy treatments. https://icvi.org.uk/ however there are also lots of other good cancer charities in the UK and elsewhere, some of which also study immunotherapy.

What are some of the lesser known things that seem to be linked to getting cancer, aside from things like sun damage to skin, and smoking and so forth ?

Thanks for the question, some foods such as smoked or processed meat are linked to an increased risk of cancer. Some pathogens such as Epstein Barr Virus or Helicobacter Pylori are also linked to the aetiology of specific cancers. There can also be heritable factors (gene alleles) that increase the likelihood of cancer. It can be difficult to measure the relative impact of environmental and genetic factors that result in the onset of a given cancer.

I actually knew about the processed meats, and I have been deliberately avoiding them.

Do we know which gene alleles to look for ?

There are well known genes with particular alleles associated with the onset of cancer. For example BCRA alleles are the most common hereditary cause of breast cancer. The BCRA genes make proteins involved in repairing damaged DNA and mutated versions of BCRA genes can prevent this repair. This in turn leads to mutations in cells which can drive uncontrolled cell division and the development of tumours. These gene alleles are heritable and a family history of cancer may be indicative of a gene allele that predisposes to cancer. GP's and genetic councillors should be able to explain the likelihood of inherited risk of cancer.

What do we mean by processed meats

Processed meat includes meat that isn't sold fresh but is instead cured, salted, smoked, or otherwise preserved - for example bacon, sausages, hot dogs, ham, salami, and pepperoni.

Hi Doc, do you eat processed meat given what you know?

I limit the processed meat I eat -I probably do so once every few months.

Hey Doc!

I was wondering what the best way to strengthen the immune system would be. We all know that exercise and diet are beneficial, but are there any specific ones?

I'd also like to request book recommendations, even if they're unrelated to your field.

Thank you very much!

A healthy lifestyle, described in some of my other answers, is the best way to maintain a strong and balanced immune system in people who are otherwise not suffering from illness. The anti-inflammatory properties of phytochemicals present in fruit and vegetables, along with vitamin D supplementation may be helpful to manage inflammation and resolve immune responses, for example to acute respiratory infections, especially for people who are deficient in vitamin D. For people who are already ill with chronic diseases such as cancer it may not be possible to strengthen the immune system in this way, at least not without also using powerful immunotherapies prescribed by an Oncologist.

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For books on the immune system I would recommend 'Immune' by Philipp Dettmer. For a science book unrelated to immunology I wold recommend 'The Selfish gene' by Richard Dawkins.

Thank you for responding!

Given the amount of information in your field, I'm curious how you approach learning.

What strategies do you employ?

You're welcome.

That's a good question - my approach to learning is to focus on a specific area whilst allowing myself some time to 'learn around the topic' - its surprising how seemingly unrelated fields of study can intersect with one another. I also find it useful to access the expertise of other people and different sources of information, lectures, papers conversations with colleagues etc. I think its important to be patient when learning new information and open to being being proven wrong.

Are there any commonly held beliefs regarding certain activities, foods or supplements that can boost immunity but in reality don't.

or to phrase it a bit better, are there any immunity boosting myths that you think should be challenged?

Good question, the main myth is probably that the immune system of healthy people need to be boosted at all. The immune system is a tightly controlled system in which too much activation can be as bad as too little. Avoiding stress and unhealthy dietary choices and the regular intake of fruit and vegetables are likely more important to maintaining a healthy immune system.

Another myth is that supplementation will necessarily result in increased concentrations of a given vitamin or other compound. Our gut controls the amount of a substance that is absorbed from our diet, and our liver metabolises much of what is absorbed. It often isn't clear how best to increase the concentration of something (for example vitamin D) via supplementation. Some approaches involve daily vitamin D supplementation and other intermittent high dose vitamin D. Regardless of the approach, the range of serum vitamin D (the amount present in our blood) is very tightly controlled.

Studies have shown that exercise can have varied effects on markers of immune function (markers are used to infer how the immune or inflammatory system may function). Some studies suggest that regular light exercise may reduce inflammation whilst intense exercise may suppress immune function. Whether these observations have practical implications for peoples health isn't yet clear.

A treatment for a specific cancer? Or all cancer?

Immunotherapy is currently used to treated numerous different cancers. Immunotherapy typically depends upon cells called 'T-cells' which identify and kill tumour cells. Although Immunotherapy has been very successful for some patients with cancers such as Melanoma, Lung cancer or B-cell lymphoma it fails to work in many patients and is largely ineffective against some cancers. I'm interested in how to improve T-cell function, especially using safe, low cost interventions involving diet or the gut microbiome.

Hello,

I currently going through tandem stem cell transplants for testicular cancer. I was wondering if there has been any research or trials using T cells to treat testicular cancer? I have read about trials with ovarian cancer which is also a germ cell tumor. And I haven’t heard about the Epstein Barr virus link with cancer. But I do have the virus in me and it was coincidentally elevated after my first stem cell transplant. I go in for the second transplant Friday.

As far as I can tell there are few recent studies researching the ability of T-cells to target testicular cancer. There are some recent studies related to Ovarian cancer however immunotherapy is not currently very effective against Ovarian cancer.

Oh is that monoclonal antibodies , I thought they weren't effective in their last trial

Monoclonal antibodies targeting 'immune checkpoints' help keep the immune system 'switched on' and have proven very effective for some patients with some cancers. Research is underway to improve how they work so that more people can benefit.

What does 'inmune checkpoints' mean and how can they be controlled through antibodies? I know about antibodies used for the opposite: to 'switch off' the immune system for example in cases of autoimmune disease. But how does one make it stronger against cancer?

Also, can we use polyclonal antibodies as therapy? Or even make our body naturally generate antibodies to help the process? I understand that we already create antibodies against cancerous cells, but that those cells have the power to attenuate the immune response. Could be build immunization against this attenuation?

If our immune system is over activated it may cause damage to healthy tissue, induce autoimmune disease or even harm itself. 'Immune checkpoints' are receptors on immune cells, particularly T-cells, which switch the T-cell of and maintain homeostasis. Tumour evolves mechanisms to hijack this system (if they don't the tumour may be eradicated) effectively switching off T-cells so they can't kill tumour cells. Monoclonal antibodies (called checkpoint inhibitors)have been developed to specifically bind to the checkpoint receptors and prevent them being used by the tumour cells. The T-cells remain 'switched on' to kill tumour cells. Unsurprisingly blocking these checkpoint receptors massively accelerates the immune response and can cause autoimmune reactions such s colitis. Sometimes these reactions are so serious that the patient needs to stop treatment with the checkpoint inhibitors.

What effect do you think CRISPR-Cass9 and the possible solving of the protein folding problem will have on medicine and specifically on cancer therapy?

CRISPR-Cass9 may help to gene edit T-cells. This could be useful for a Immunotherapy involving the adoptive transfer of T-cells into cancer patients. This involves removing patient T-cells and stimulating or engineering them so that they can target tumour cells more effectively, before reintroduction into the patient. CRISPR-Cass-9 can be used to switch of certain genes which may improve T-cell function or prevent the onset of exhaustion, which limits their function.

Solving the protein folding problem involves being able to predict how a simple sequence of amino acids (called a peptide) will fold into a functional protein. Understanding how this works might help with the design of synthetic cytokines. Cytokines are proteins used by the immune system to communicate and kill tumour cells. The generation of improved, synthetic cytokines may help target immune responses towards tumour cell killing.

These scientific advances are in early stages of development and its too early to say whether or not they can be used to improve cancer therapy.

This may sound stupid but has anyone tried injecting a virus directly into the cluster of cancer cells? Like the flu or something? Also what happens when you inject vaccines for other viruses (especially already recognized viruses that a person should already have an immune response for) into cancer infected areas?

These are good questions. Scientists are developing a therapy using 'oncolytic viruses' - these are viral constructs capable of entering tumour cells and lysing them. They have great promise as therapies - the difficulty is getting them into the tumour microenvironment (which consists of tumour cells and surrounding 'supportive' cells).

Some tumour microenvironment have T-cells specific to viruses such as influenza. It isn't clear what these cells are doing in the tumour (since they target cells infected with influenza) but its possible that they can be harnessed to support cancer immunotherapy.

More generally there is some evidence that raising immune responses to unrelated pathogens (or harmless preparations of them) can have a training effect on the immune system, making it more able to target tumours upon the administration of immunotherapy. This is an active area of research intended to improve existing immunotherapies for cancer.

how near are we in finding cure to cancer ?

Its a common misconception that we do not yet have a cure for cancer. There are actually lots of effective therapies, many of which are curative. The best example is the surgical removal of the tumour. Immunotherapy for cancer has also recently demonstrated an ability to eradicate tumours in a small number of patients.

Two issues that need to be addressed are the eventual return of cancer, sometimes years after the primary tumour has gone, and some very aggressive cancers such as pancreatic cancer, which are diagnosed too late and currently have no curative therapies. Despite this some pancreatic cancer patients go into long term remission after treatment which provides hope aggressive cancers such as this are curative in principle.

Are there any supplements that can boost your T-cells to help prevent cancer development?

Lots of different fruit and vegetables are probably the best 'supplement' we could take. fruits and vegetables including apples, berries, cauliflower, garlic, carrots etc contain multiple different vitamins and compounds called phytochemicals, each with various immune modulatory and anti-inflammatory properties. They also contain fibre which can support a healthy gut microbiota. Good gut health and low background inflammation may be the best way to help T-cells prevent cancer development.

Well İ do well then, eat garlic and friuts and vegs., daily since living in Turkey for the past 16 years. The more detailed question would be the phamacies here have bottled suplements that claim to boast T-cells, do you believe this also would be helpful or probally just better to eat and consume naturaly?

Generally I think its better to derive all the micronutrients we need from our diets whenever possible. Some people may have deficiencies in a particular vitamin or mineral (such as vitamin D or Iron) and supplementation may be a good way to address this. However in such cases I would recommend discussing the subject with your GP.

What makes T cells especially suited to fight cancer?

T-cells have the ability to infiltrate into tumours and kill tumour cells. They can subsequently divide to form memory cells capable of identifying the tumour and eradicating it with greater efficiency. T-cells can also be engineered to improve their cancer killing properties. This allows us to isolate patient T-cells, improve them and re-administer them into the patient.

The ability of T-cells to kill tumour cells results in the evolution of countermeasure by the tumour designed to 'switch off' or 'exhaust' T-cell function. Immunotherapy designed to counter this has been very successful in treating tumours such as Melanoma and Lung cancer.

Hi! I’m going through what I guess I would call my “first round” of immunotherapy for metastatic melanoma. I’ve had several adverse reactions (I got colitis and immuno-hepatitis or whatever that’s called) but now, thankfully I’m at a point in my treatment where I feel normal and can even exercise again.

My question is maybe a bad one, I don’t know, but are there still studies being done on long term effects of immunotherapy treatment? Before treatment started I got the standard warning that I could get immune system diseases (and I have) but do you know if there are any further studies to help learn why some people get them and some don’t?

Thank you for all the work you do!

Hi, thanks.

Colitis and hepatitis are fairly common immune related adverse events (IRAEs) associated with Immunotherapy using checkpoint inhibition. Sometimes they're associated with the efficacy of the treatment. In general, the type of IRAE will depend upon the type of immunotherapy, the cancer type and the patient. Some factors which influence the onset of IRAE include the composition of the gut microbiome (which is also associated with response), age, weight, presence of existing co morbidities and whether or not the patient smokes.

This is an active area of research - if we can minimise IRAE more patients will be able to be treated with immunotherapy and fewer patients will have need to cease therapy.

Patients have been treated with this type of immunotherapy for a number of years now, so we're beginning to see follow up of over five years, but its true that we don't know the long term health impact.

Hi 👋🏼 and thanks for doing the AMA. I took yervoy + opdivo for stage 3C melanoma and have been cancer free for 5 years now. You mention long term health impact. Could there be affects of the treatment that aren’t seen within 5 years? Seems like a long time to have your body go through a delayed response.

Hi, the answer is - I don't know. Combination immunotherapy of the kind you took is very powerful, it dramatically accelerates T-cell immune reactivity. Its possible that your T-cells are now 'primed' which may make them more susceptible to break tolerance and respond to self antigen upon future stresses such as infection or inflammation. This could promote autoimmune disease - perhaps simliar to the immune related adverse events that can occur in patients treated with yervoy/opdivo combination therapy. But again, I don't know since the therapy is still fairly new. In the meantime its great that it has been effective for treating your melanoma :-)

What can one do to reduce the risk of getting cancer as one ages besides a good diet?

Thanks for the question. Probably the best thing we can do, other than make good lifestyle choices (factoring in diet, exercise, alcohol consumption, smoking, stress), is regular check ups, especially for individuals at greater risk of developing cancer. Diagnosing a cancer earlier makes it easier to successfully treat.

I'm a former immunotherapy researcher who worked on CAR T cells before switching my focus to nanoparticle vaccines that target DCs. I was outwardly called dumb for moving my interest away from CARs; they are such a hot topic. Do you have any interest in CAR T cells, whether directly or applying your research to them?

I'm interested in how CAR T-cells can be made more effective, particularly after they've been re introduced into the patient. How the gut microbiome might influence the efficacy and maintenance of CAR-T-cells is interesting to me.

However CAR T-cells have not currently demonstrated efficacy against most solid tumours and are inherently expensive to produce. I'm more interested in safe and cheap methods to enhance T-cell responses since more people are likely to benefit.

Is there any benefit to cancer prevention from over the counters like resveratrol, NMH, Quercitin as a supplemental? In addition to healthy lifestyle, keeping weight down, regular exercise, etc?

These phytochemicals are very interesting and have diverse immune and anti inflammatory properties. However phyotchemical supplements have not been proven to prevent cancer and, for some phytochemicals, its possible to obtain physiologically relevant quantities from a healthy diet. For example Quercitin is present in a wide ranges of fruits and vegetables. The benefit of gaining phytochemicals from fruits and vegetables is that each one typically has a combination of these compounds in addition to being a source of vitamins and fibre.

Hello Dr Smith, thank you for taking the time to be here with us. I really appreciate it.

1. Based on your expertise, is gene therapy ready to be directly use on cancer treatment nowadays? I heard that many people rave about JAK2 gene therapy.
2. May I read your previous publication please? I would like to study more about the T-reg role in cancer development.
3. How do you manage your project during Covid time, since every movement is restricted?

Thanks! Have a good day :)

Hi, thanks for the questions...

1: Gene therapy has promise as a cancer treatment. My background is in Immunology/cancer Immunotherapy and gene therapy of T-cells has the potential to improve their function, durability and/or limit toxicity. This process involves removing T-cells from patients, engineering them with gene therapy and re introducing them into the patient. Gene therapy directly into tumour cells may be hampered by the difficulty of accessing the tumour and may be more suited to tumours such as melanoma rather than tumours such as pancreatic or colon cancer.

2: This is my recent publication summarising how to improve T-cell function against cancer: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708201/ However it doesn't focus on T-regs. Here's a review on T-regs (not written by me) https://pubmed.ncbi.nlm.nih.gov/23199321/

3: COVID was initially very disruptive to our research since most of us no longer had access to our laboratories and there is a limit to how much we can achieve at home! Lots of projects were essentially on hold. After the first lockdown in the UK we returned to the lab and got back to work with various safety measures in place.

Do you believe that there is a possibility of cures being suppressed to continue only treating the disease, for say. Financial gain?

Common theory amongst common everyday folk. Never asked a doc about it though.

No, I don't. Hypothetically its possible in a limited way, but generally I think its unlikely. For an improved therapy/cure to be suppressed it must first be proven. This is a very expensive process and there will be considerable incentive to monetise the new treatment. Such improved treatments will be very lucrative for a pharmaceutical company and if they don't take advantage of it some other company will, especially after patents expire. Ultimately being first is too important to a pharmaceutical company.

What are the common side effects you see with immunotherapy? For those who have strong reactions/side effects (body aches, numbness, pain, nausea, etc.) what are some things they can do to combat this since immunotherapy is often a long term treatment?

Good question, it depends upon the type of immunotherapy since different therapies have a different array of adverse events. It also depends upon the patient.

The type of adverse effect will determine which approaches are used to ameliorate them. Cancer patients who are otherwise relatively 'fit' may also be more able to tolerate some adverse events/side effects.

For example, Immunotherapy using checkpoint inhibition is sometimes associated with colitis. Medicine used to treat colitis can also be used to treat Immunotherapy induced colitis, for example corticosteroids. The same approach may be used for other adverse events associated with immunotherapy.

For less serious adverse events, such as body aches, numbness and nausea, there may be complementary approaches to reduce symptoms. Such approaches should be discussed with the oncologist. Nutritional supplementation or certain approaches may also be advantageous in managing side effects, particularly those involving nausea and maintaining adequate intake of nutrition, and patients should discuss this with a nutritionist who specialises in cancer.

Does this treatment show any promise for pancreatic cancer?

Immunotherapy has not yet demonstrated enough efficacy to be licensed to treat pancreatic cancer however a number of case studies have shown that immunotherapy can, in principle, be effective. Research to improve the immune response against pancreatic cancer, alongside ways to detect it at earlier stages of development, will hopefully allow pancreatic cancer patients to realise the improvements in treatment currently available for some patients with more immunogenic cancers such as Melanoma.

Wait what?? I have a family member that was diagnosed with stage 3b pancreatic cancer that had a whipple done but still found traces in distant lymph nodes that went on keytruda and is still alive 2+ years later after being given a few months to live post surgery.

Hi, metastatic tumour cells will behave differently to the primary tumour and may be more susceptible to immunotherapy such as with keytruda. It is also true that some pancreatic cancer patients have benefited from immunotherapies such as keytruda when given 'off label'. Immunotherapy is not yet approved for the general treatment of pancreatic cancer.

Hi there!
8 year survivor here. I am currently about 9 months into a monthly single immunotherapy for melanoma, (Third recurrence) and am experiencing a response stronger than anyone on my team had expected.
Basically things are going very well to the point where I hope to be declared in remission (again) within the next 6 months.

My question is in regards to prolonged fasting in order to 'reset' your immune system.
I've heard that upon fasting for 48-72 hours, your body enters starvation mode and starts to break down all the old/damaged white blood cells and other immune system components. Then upon exiting the fast, your body begins to create new healthy white blood cells etc, thus reinvigorating/re energizing your immune system.

So... is there evidence that this is actually what happens during an extended fast, and do/would you recommend it as a component or companion to an immunotherapy regimen?

Thanks for what you do, if it weren't for you and others like you, I doubt I'd be here right now.

Hi, its good to hear that your immunotherapy seems to be working. Thanks for the question too. There is some experimental evidence indicating that a ketogenic diet with intermittent fasting may help checkpoint inhibitor immunotherapy however this is pre clinical research: https://pubmed.ncbi.nlm.nih.gov/33320838/

We cannot draw conclusions about whether this approach would be advantageous for cancer patients. Diets involving dietary restriction may work by altering how T-cells utilise energy or by restricting essential compounds such as amino acids (e.g glutamine or methionine) to tumour cells. Again, these approaches, whilst exciting, are not currently used clinically. I would recommend that you talk to your oncologist if you're thinking of making changes to your diet, especially given that your team already seem pleased with your response.

How does your work compare to Gerson Therapy?

Good question. As far as I am aware their is no scientific proof supporting the use of Gerson therapy to treat cancer. Anyone who wishes to use this approach should seek the advice of their doctor.

Its well established that the adoption of a healthy lifestyle can help prevent cancer. Such approaches are unlikely to be decisive in curing people who already have cancer. Immunotherapy uses the immune system to target and kill tumours. A number of immunotherapies have been licenced to treat cancer in countries such as the UK and USA.

Some clinical studies indicate that diet and our gut microbiomes may influence the effectiveness of cancer immunotherapy but it is not yet clear how we should use these tools to improve treatments. This is an active area of research. Any complementary or alternative diets/supplementation should be discussed with a GP and/or Oncologist especially since some approaches have the potential to do more harm than good.

Hi Dr Pete,

I have a question about the immunotherapy and Hashimoto Disease. My wife suffers from it and I’m curious if there is anything you can say/share regarding her condition. How can we make it better ? Or is there a way or treatment which can fix her immune system. ( She is on thyroid pills but it is definitely reducing the quality of life ) thank you for your time.

Hi I'm sorry to hear this. This is not within my area of expertise. I can say that the study of immunology and its translation into immunotherapies for cancer and autoimmune disease is in very exciting period with discoveries having significant 'cross over' potential. Hopefully new treatments will be made available.

I'm very sorry if I'm off the rails here, Dr Smith, but what academic sources you use to browse research papers? Where do you gather new information regarding your field?

Hi,

Pubmed is my preferred choice: https://pubmed.ncbi.nlm.nih.gov/

Once you've found a paper of interest you can scroll down past the abstract for related papers and references and go from there.

I just watched Jim Allison: Breakthough on Public Television. Is a lot of your research based upon foundations that he helped formulate years ago, or are there entirely new angles that have rendered his assertions antiquated or misguided?

Cutting edge Immunotherapy research builds upon the findings made by Professor Allison and other Immunologists. The field is advancing very quickly with lots of exciting developments that utilise earlier immunology research.

I'm a bit late but I thought I'd post a question anyway.

I had prostate cancer at 38, and successfully nuked it with brachytherapy. Obviously that treatment is specific to where the cancer is.

With your treatments, will the T cells be able to take on any cancer, regardless of type and location?

Hi, good question. Ultimately the aim is to use T-cells to treat all cancers however specific immunotherapeutic approaches will be needed depending upon the tumour in question. A growing number of tumours can be treated this way but lots of work remains to be done, especially for 'non immunogenic tumours' such as pancreatic cancer.

Hi! Currently a lot of research is done for different kinds of advanced therapeutic medicinal products (ATMP's), for example CAR-T cell therapies of which multiple have been market approved, dendritic cell therapy and oncolyticvirus therapies. Many therapies have clinically pretty good outcomes, but many don't make it to, or past the first few years of market authorisation. What do see as the biggest current hurdles and where do you see ATMP's going the next 10 to 20 years?

Hi, thanks for the question. The main issues for the next 10-20 years will likely include 1: addressing the cost of ATMPs 2: addressing the issues of immune related adverse effects associated with their use, especially for combination therapy 3: their efficacy in treating currently 'non immunogenic' tumours 4: identifying which patients will benefit from which therapies, particularly as/if more options are available from the immunotherapy 'toolbox' and 5: understanding the best/most appropriate trial design and patient selection to test new candidate therapies.

Is the use of mRNA vaccines to target cancer proteins being investigated? Do you think it'll lead anywhere?

Yes, mRNA vaccines are being studied for use in combination with other immunotherapies. They have the potential to 'direct' the immune response activated by immunotherapy so that it more effectively targets the tumour. The success of this approach may depend upon the extent to which tumour expresses antigen from which the mRNA can be made. This approach is still in development but in my opinion has a good chance to help at least some people with particular cancers such as melanoma.

Asking here, since it's topical:

A new customer of mine is working on mrna cancer treatments. From reading up on it and discussing it with them, it seems like you need to adapt this for every patient. How does that fall in line with currently testing requirements for new medication? We could hardly have big multi year trials for every patient, right?

I think this refers to the use of 'neoantigen' which are unique to each patient. In such cases the neoantigen is identified and sequenced and then placed into an mRNA 'construct'. In terms of testing new medication the mRNA construct and vaccination procedure is tested for safety. The addition of different neoantigen to this platform is thought to be unlikely to generate adverse reactions since the neoantigen is only present in the tumour. Unlike prophylatic vaccination of healthy people using mRNA (such as for COVID) cancer patients may be seriously ill and the analysis relating to benefit and risks is different.

Thanks for your reply! As a follow-up, do you mean that your work is also about enhancing t-cells to be able to better kill cancer cells? I (being nowhere near in the field) always assumed immune response to cancer was a problem of identification and not whether t-cells can induce apoptosis on cancer cells.

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Thanks for the AmA, I love this subject!

You're welcome.

T-cells face two problems. The first is that of identification - tumour cells are 'self' so the immune system should ignore them. However they are 'altered self' and their are often sufficient differences for our T-cells to target and kill tumour cells. In fact this is what happens most of the time - T-cells identify transformed or early tumour cells and eradicate them and we are unaware that the tumour even existed. Clinically diagnosed tumours have already survived this immune response, evolved mechanisms to escape and become established.

Which leads to the second problem for T-cells. Tumours that evolve to escape the immune response often do so by inhibiting, exhausting and/or switching of the T-cell response so by the time a patient is diagnosed with cancer their immune system has already failed - the T-cells are unable to induce apoptosis of tumour cells. This is where immunotherapy can be used to reactivate, enhance and/or re target the immune response to defeat the tumour.

My research is focused on how best to support the T-cells so that once they target the tumour they continue to proliferate and persist as potent killer T-cells, rather than become exhausted and unresponsive to Immunotherapy treatment.

Hello,

I've been diagnosed with Ankylosing Spondylitis (AS) and have been receiving Infliximab (Remsima to be precise).

Could you explain what TNF-α does in layman's terms?

What is the most exciting development regarding immunotherapy in your opinion?

How come the (human) immune system is so complex?

Hi, thanks for the questions.

TNF alpha is a cytokine. Cytokines are proteins released by cells to allow them to communicate with one another and to mediate 'functional responses'. This is done by binding to specific receptors present on other cells (cytokine secretion from some cells and receptor expression on other cells is co ordinated and can be either induced by stimuli or constitutive /always present). Binding of the receptor initiates signaling cascades within the cell which dramatically alters the expression of different gene and thus mediates the cytokines effect.

TNF-alpha mediates functional responses such as cell death, inflammation, fever or cellular proliferation. the type of functional response is dependent upon which cell is releasing the cytokine, which cell is responding, which receptor on the cell has bound the cytokine (TNF-alpha binds to two different receptors which initiate different programs of gene expression) and the environment in which it acts (other cells and other cytokines). In the context of autoimmune disease TNF-alpha exacerbates autoimmune reactions and can be inhibited with Infliximab. I hope that is helpful.

The most exciting development? There are lots but the observation that our immune function is profoundly effected by our gut microbiomes is very exciting. The generation of synthetic cytokines is also an amazing development.

Why is the human immune system so complex? I don't know. Perhaps because its very smart and needs to be so to protect us from a diverse range of challenges. It evolved from early mechanisms to control development and wound repair but the subsequent evolution of the adaptive immune system (T-cells and B-cells) has added significant complexity since the ability to adapt is inherently complex from a design/engineering point of view.

Is there some kind of centralized registry for immunotherapy trials? I have a loved one who just finished treatment for a cancer that is likely to recur. It would be great if there were some kind of centralized system to see if there is a trial that is a good fit.(In the US though, sadly.)

https://clinicaltrials.gov/

This should be what you're looking for. It takes a while to figure out the best way to use the search function.

I hope its helpful :-)

I’ve been recently diagnosed with reoccurrence stage four colon cancer, metastasis of the pelvis. I’m 36 and in good physical shape, should I know of any other treatments outside the chemo I’m starting next month?

Sorry to hear about your diagnosis. I would recommend that you speak to your GP or oncologist about any potential clinical trials or other approaches that might be available to you. Good luck with your treatment.

What’s the risk of accidentally pointing the immune system at self instead of the cancer? How do you ensure specificity?

This is a real risk and a limiting factor on some, otherwise effective, immunotherapies. The best immunotherapy to date is associated with the onset of autoimmune related adverse events, although these often last only as long as the immunotherapy is administered.

A number of methods are under investigation to more effectively target immunotherapy into the tumour. These include the use of antibodies targeting receptors expressed only on tumour cells and activating immunotherapies only once they reach the tumour microenvironment.

What is the most exciting medical development you’ve heard about recently and should we be excited also?

Hi - good question!

There are a few -

1: The observation that immune function is regulated by our gut microbiomes - against this offers a new avenue by which we can regulate and control our immune responses in health and disease.

2: The genetic engineering of porcine organs for transplantation. This has the potential to increase the availability of organs which is vital since demand significantly outstrips supply.

3: CRISPR-cass-9 genetic engineering for the above but also to engineer T-cells for adoptive T-cell therapy.

4: The development of synthetic cytokines and improvements in targeting them towards tumours. This potentially offers a new level of immunological control.

I think you should be excited about the above (especially number 1).

What are some practical ways in which we can boost our immune system, for example are there any supplements we can take?

Good question, for people who are relatively healthy it may not be necessary to 'boost' their immune system. Its more important to maintain a balance. This will likely involve a varied diet with lots of fruit and vegetables, dietary fibre and low quantities of processed meat and sugar. Regular exercise and sleep may also help. Supplements may not be necessary but maintaining the bodies levels of vitamin D is important in reducing inflammation and maintaining immune homeostasis.

Is it true the majority of our immune system is in our gut?

The majority of our immune system (at least immune cells such as lymphocytes and myeloid cells) is in barrier sites such as the skin and mucosal surfaces. Given the gut is our largest mucosal surface it is true to say that the majority is located in the gut.

Any thoughts on LAG-3?

LAG-3 is an immune checkpoint present on T-cells and hijacked by tumour cells to evade immune responses. It might be the most promising target for monoclonal antibody 'checkpoint inhibitors' outside of PD-1/PDL-1 and CTLA-4. Even if blocking LAG-3 with monoclonal antibodies isn't effective as a single agent anti-LAG-3 monoclonals will increase our immunotherapy 'tool box' and have promise in combination with anti-PD-1, for example to treat melanoma.

How can we support our immune system to prevent cancer as we age? Specific supplements, exercise?

Maintaining a healthy diet and weight whilst exercising and avoiding processed food, sugar, alcohol and smoking will help. In terms of specific exercise I think regular exercise e.g. swimming, is beneficial to general health, particularly as people age. Epidemiological studies and meta analysis attempting to identify an association between particular foods (e.g green tea) and the incidence of cancer fail to identify consistent benefits - this can be because there is no benefit or it is not yet possible to control of confounding factors. As such caution is needed before using specific supplements for putative anti cancer properties, especially since they may also have adverse effects.

Thanks for your AMA and for the work you do in the field of research.

Barring current "western" treatments for cancer, some turn to Naturopaths to support their cancer therapy or to improve it while simultaneously undergoing treatment from an oncologist.

What are your thoughts on naturopathic treatments such as high dose vitamin C drips, mistletoe injections, or supplements such as EMIQ, berberine, tumeric, etc?

If your response includes issues with evidence for such things, is it worth supporting more research in those areas? Or is this simply an area of snake oil?

Hi, thanks for the question. 'Naturopathic treatments' represent a large number of different compounds and approaches whose effects may also differ from person to person and in different disease settings.

I do not think these approaches, including of the kind you list, will be useful in treating cancer. Its possible that they're helpful in managing the toxicities associated with chemotherapy or immunotherapy. If so part of their efficacy may be due to a placebo and/or 'TLC' effect. There is also some epidemiological data suggesting that some dietary compounds may prevent the onset of cancer - but not treat existing cancers. Anyone thinking of adopting a naturopathic approach should first speak to their oncologist.

In terms of future research, there is evidence that immunotherapy may be significantly influenced by dietary factors and more research is needed in this area. For example, recent studies suggest that high dose vitamin C may improve the efficacy of checkpoint inhibitor immunotherapy. However, its important to note that this is pre clinical research and that the utility of high dose vitamin C dependent upon the established efficacy of Immunotherapy.

Hi Dr Smith. My father is starting immunotherapy for Stage 4 lung cancer. The doctors discussed some of the side effects and that steroids are sometimes required to counteract the side effects. Is any work being done to reduce side effects immunotherapy? Is that possible?

Hi, yes the side effects of immunotherapy are referred to as 'immune related adverse events' (IRAE). They are a significant factor limiting who can be treated with immunotherapy and which combination immunotherapies can improve efficacy without greatly increasing IRAE. In addition to developing better ways to manage the IRAE new combinations intended to enhance the efficacy of immunotherapy without adding the the toxicity are under investigation.

Hello! thanks for doing this.

Do you think cis-acting bispecifics (such as recently approved Rybrevant) will take a bigger place in the field of oncoimmunology treatment within the next decade?

Thanks for the question, I think that bispecifics have a lot of potential, particularly in improving targeting and reducing 'off target' effects. The limiting factor may be the discovery of two effective targets, such as those used for Rybrevant, and the number of patients who can benefit when it requires the expression of specific receptors.

What is your opinion on oncolytic viruses as immunotherapy?

Hi, they're potentially very promising, especially in inducing a process called 'immunogenic cell death' - a way of killing tumour cells which activates the immune system. They also have the potential to deliver genes into the tumour microenvironment whose gene products may activate anti-tumour immunity. One of the issues with oncolytic viruses involves effectively targeting them to tumour cells and preventing anti-oncolytic virus immune responses from clearing the oncolytic virus before it reaches the tumour.

Are there studies that take into account vitamin D levels? I'm wondering if lower vitamin D increases risk of certain cancers. Has anyone weighed the risks of vitamin D supplement vs vitamin D from sun exposure. Also, geographically people's daily sun exposure & cancer rates

Thanks for your time

Vitamin D is associated with regulating immune responses and may be useful for reducing the onset or severity of some types of autoimmune disease. Paradoxically, vitamin D may also help improve the efficacy of cancer immunotherapy, although it is too soon to draw conclusions. There is some promising data in relation to levels of serum vitamin D and melanoma. The effect of sun exposure and and sun burn with various skin cancers is well established.

I know your focus is primarily on cancer, but as someone with an autoimmune disease who's been put onto everything from 'Mercaptopurine' to 'Mycophenolate Mofetil' to try to get me off of Prednisone after 8 years of it being the only thing that works. Do you happen to know of any exciting new research or breakthroughs involving the Autoimmune sector amongst your colleagues?

It often seems like autoimmune issues are less understood and less researched/talked about than most cancers these days.

One of the problems with T-cell immunity against cancers is that the T-cells become 'exhausted' due to chronic activation by the presence of the tumour, and stop functioning as they should. A problem in some autoimmune diseases is that self reactive T-cells continue to function, despite being exhausted. Immunologists are actively studying why T-cells behave differently in each disease despite exhibiting the same 'exhausted' characteristics. Once this is understood we will hopefully be able to keep the anti-tumour T-cells switched on and the autoimmune T-cells switched off. By studying one disease we might find solutions to others.

Hi Pete. My Dad had Sezary T-Cell Lymphoma and had immunotherapy in 2009. He subsequently got B-cell lymphoma but that got sorted too. He’s still going. Touch wood. He has regular immunoglobulin top-ups at Hammersmith. My question is whether this is hereditary or just bad luck? Is there any way I can screen for it?

Finally, have there been improvements in how to apply the treatment? They basically had to nearly kill him with chemo and then do the stem cell infusions. He then got really bad GVHD. It was a rocky road. All worth it obviously but has patient experience improved since then?

Thanks for all you do.

Hi, thanks for the comment, its good to hear of your dads successful treatment. If his cancers are hereditary it might be possible to trace this by investigating your family history with your GP or a genetic councillor.

I am not familiar with the specific treatments your dad had but I can say that both treatments and how to target them to the tumour are improving as are treatments to manage the consequences such as GVHD. Ultimately the more we learn about the immune system the more we can apply this knowledge to help patients.

Ok. Do we have a chance to see a cure for cancer in the next 20-30 years?

Hi, there are already a number of cures for cancer - the best example is probably surgery. The problem is these don't work for all people.

Immunotherapy for cancer has demonstrated significant improvements in treatment for some people, with some cancers. A minority of patients demonstrate long term remission. The challenge now is to improve immunotherapy treatments so more people can benefit and so is effective against more cancers. This, paired with earlier diagnosis offers the potential for significantly improved outcomes for patients.

How can one keep their natural immune system healthy to avoid colds and flu, while also being on regular immunosuppressant steroids and MMF due to an underlying autoimmune disease?

This isn't really my area - you should speak to you're GP - but the general principles of a healthy lifestyle are probably applicable here (some phytochemicals in foods and drinks such as green tea are thought to have antiviral properties but this has not been studied in clinical trials). More generally, the first defence against infection is not our immune system but barriers such as the skin and mucosal surfaces. With that in mind measures such as antiviral hand wash, masks etc (the kind of things to reduce the chance of catching covid) might be recommended for other respiratory infections.

About 3 years ago, my wife died of Familial adenomatous polyposis and my kids are at risk as well. Have there been any changes to look towards on this? She was on opdivo with no positive results.

Hi, I'm not particularly familiar with Familial adenomatous polyposis but my understanding is that the ensuing colorectal cancers can be poorly responsive to checkpoint inhibition such as with Opdvio. However Opdivo (Nivolumab) is being studied in numerous clinical trials with different agents intended to improve its efficacy. Hopefully this will increase the number of tumours against which it is effective and the number of patients who can benefit.

What are T cells ? Are they the same as B cells ?

B cells are memory cells and T cells are killer or reactive cells afaik could be talking nonsense though.

T-cells and B-cells represent the two 'arms' of the adaptive immune response. B-cells produce antibodies. The antibodies can be secreted from the B-cell and are capable of binding to antigen, such as the antigen on the surface of viruses, and in so doing inactivate the virus.

T-cells identify and target infected cells or tumour cells and kill them. This limits the spread of the virus or reduces the size of the tumour. Another type of T-cell, referred to as a 'helper cell' co-ordinates both the B-cell/antibody and T-cell/killing functions so that they can work on concert.

Can you please comment about the different characteristics and biological effects of PD-1 antibodies such as pembrolizumab and nivolumab vs. PD-L1 antibodies such as atezolizumab, avelumab, and durvalumab?

PDL-1 is present on tumour cells and antigen presenting cells, it binds to PD-1 present on T-cells and instructs the T-cell to 'switch itself off'. This negative feedback loop has evolved to prevent chronically activated immune responses and autoimmune disease but its hijacked by the tumour to evade the anti-tumour immune response.

Since PD-1 and PDL-1 are on different cells we should expect their respective checkpoint inhibitors to have different effects dependent upon the nature of this expression and the patient immune response. Ultimately all of the antibodies you list block PDL-1/PD-1 interaction and should help licence T-cells to target tumours.

What's your favourite dinosaur?

Triceratops. Obviously.

How important is selenium in combatting cancer? Zinc? Is nutritional status even recognized as having importance?. Where I live, it's never even mentioned.

Its difficult to say how important specific minerals are in combatting cancer, other to say that they are essential to general health. Nutritional status may begin to play a more central role in patient health, particularly in the context of cancer immunotherapy.

Brother ( 50 yrs) has stage 4 colon cancer, he's tried experimental 13 hr Hipec, didn't work what we had hoped. Done two chemo + 1 radiation & now doing next chemo phase ( ranging from 8 to 16 weeks each) diagnosed 3 yrs ago 😔 Always eaten unhealthy sadly

What are the three things I should know that could help him? Please 🙏

Lastly, he can't sleep longer than 45 min, would cannabis oil be of good use in calming him down so his brain can sleep?

Be well 🤗 Dr. Pete Smith

Hi, I'm sorry to hear about your brother. I'm an immunologist, not a clinician, so I can't offer you advice, but I wish your brother and you the best of luck.

Hey Doc. What are the prospects for the use of t cells for castrate resistant prostate cancer?

I'm not particularly familiar with CRPC. I do know that its regarded as an immune suppressive cancer and immunotherapy has not yet been approved as a treatment. It is however an active area of research with some promise that improved immunotherapeutic treatments might be available for some patients.

This review summarises the current status of immunotherapy for CRPC: https://pubmed.ncbi.nlm.nih.gov/35327339/