Clarifying immunotherapy

- Updated on 16 March 2017 -

Friday, 3 March 2017

WE read with great interest the article “A case for immunotherapy” (Sunday Star, Feb 12). Firstly, we would like to congratulate Chin (nasopharyngeal cancer) and Wong (prostate cancer) on improvements in their condition and for their successful struggle against cancer. Many like these two men are increasingly facing up to the reality of a cancer diagnosis as its prevalence rises in the Asia-Pacific region. However, upon reading the article we also noted several disturbing points regarding their treatment which we would like to highlight here.

Firstly, immunotherapy is indeed emerging as a new and exciting breakthrough in our treatment armamentarium against cancer. Immunotherapy aims to harness or enhance the ability of our own immune system to recognise and mount an immune response against cancer cells. Indeed, over the past few years, several immune therapies such as PD-1 and PDL-1 checkpoint inhibitors have now received licensing approval from major health authorities such as the US Federal Drug Agency (FDA) and European Medicines Agency (EMA). Much time, cost and effort have gone into performing clinical trials involving thousands of patients in order to prove that these treatments are superior to current available treatments and can be safely given with acceptable side effects. Not least as these treatments are usually very costly, we need to be sure that they work before they are offered to the public.

In contrast, the HITV (Hasumi Immunotherapeutic Vaccine) treatment in combination with radiotherapy is not an FDA or EMA approved therapy. There are no large phase 2 or phase 3 clinical trials (such trials are a necessary requirement before new therapies can be approved by the regulatory authorities) that have been performed to prove that it works any better than conventional chemotherapy, radiotherapy or targeted therapy alone. Indeed, the clinical trials to explore whether cellular immunotherapy treatment such as HITV are effective are currently only in an initial stage of development and it is premature to suggest that these treatments should be offered widely to the public.

Regarding the specific cases discussed, it is already well known that radiotherapy alone can cure up to 80% of patients with stage 2 or 3 nasopharyngeal cancer. It is highly questionable whether HITV immunotherapy would have provided any additional benefit on top of highly effective treatment with radiotherapy.

In the case where prostate cancer had spread to the pelvic bone (which incidentally would make the patient stage 4 cancer, not stage 3 as reported), the article omitted to report whether the patient was receiving hormonal therapy. We would be very surprised if the patient was not receiving hormonal therapy as it is the standard treatment for stage 4 prostate cancer and is over 90% effective in controlling this disease. Coupled to radiotherapy, which confers further benefit, this makes this combination approach extremely effective for the vast majority of prostate cancer patients. Again, it would be questionable whether HITV treatment would have provided any additional benefit to this patient.

As health professionals, we fully empathise with the dilemma and plight of cancer patients who are beginning their struggle with cancer. In the midst of the shock of receiving the news of the diagnosis, frequently they will also receive conflicting advice from well-meaning friends and relatives.

Often times, patients would recoil at the mention of the word “chemotherapy” and do everything in their power to find alternative solutions. This well-meant advice, however, may not necessarily be beneficial nor accurate.

We would caution patients to consider whether any proposed treatment is backed up by proof. Claims that a particular therapy, be it immunotherapy or alternative therapy, which may act as an “adjunct” to conventional therapy must be substantiated by proof. Claims that a particular treatment is effective due to the existence of limited laboratory data is inadequate to bring it into clinical practice that requires scientific rigour.

Claims, no matter how plausible, for example the use of radiotherapy or chemotherapy to release tumour antigens to sensitise dendritic cells, must ultimately be backed by proof, which MUST come in the form of phase 3 clinical trials whereby one group of patients is exposed to the treatment and one group is not, and the former group must record an improvement in survival and/or quality of life.

Some therapies claim proof in the form of a handful of anecdotal patients who have benefited, which is insufficient and subject to bias from the person offering the therapy. Claims that a particular treatment is preferable because of minimal side-effects over conventional therapy is insufficient to justify it being recommended for use. Furthermore, many of these non-conventional immunotherapy and supplemental therapy are very costly.

Increasingly, oncologists are witnessing patients who are suffering from financial burden due to their expenditure on cancer care. We have encountered many patients who have expressed regret having spent large sums of money over ineffective cancer treatments only to be left without resources for subsequent effective therapy.

There is a huge industry revolving around the sale of non-licensed “adjunct” medical therapies or supplements and we would like to remind patients that these are fundamentally commercial entities. We strongly advise patients to be judicious when choosing the appropriate therapy for their illness and to consult an oncologist accredited in their respective national specialty register.

The good news is that as cancer therapies are becoming increasingly sophisticated, our results are improving in great strides and the side-effects are reducing significantly. The guiding principle behind modern oncology care is to prolong life while maintaining good quality of life.

In view of this, we hope patients will continue to seek professional help from their local accredited oncologist. If in doubt over a particular therapy, we simply advise patients to demand phase 3 clinical trial proof that the treatment works. Otherwise, you may just be buying hope and a feel-good placebo effect.

MALAYSIAN ONCOLOGICAL SOCIETY

In conjunction with Dr Ravindran Kanesvaran

President, Singapore Society of Oncology

http://www.thestar.com.my/opinion/letters/2017/03/03/clarifying-immunotherapy/

Friday, 10 March 2017

Keeping an open mind on ‘unproven’ treatments

Friday, 10 March 2017

Keeping an open mind on ‘unproven’ treatments

I AM writing in response to the joint letter by the Malaysian Oncological Society and the President of the Singapore Society of Oncology (The Star, March 3).

Your letter is generally well written, offering sensible cautionary advice to cancer patients about “unproven” treatments.

While I cannot offer the breadth of data you demand (“clinical trials involving thousands of patients”) I will share one data point in an in-depth manner, in the hope that you see prima facie evidence that maybe Human Initiated Therapeutic Vaccine (HITV) works after all.

And since I am “replying” to oncologists, I will convey facts accurately from medical reports and supplemented by personal notes. I hope that laymen readers will bear with me.

My mother’s recent journey with cancer started with a transurethral resection of a bladder tumour (TURBT) to remove a low-grade bladder tumour in June 2012. Soon after, she noticed blood in her urine and this led to surgery to remove her left kidney and some surrounding tissues three weeks after the TURBT.

“Invasive high-grade transitional cell carcinoma of left renal pelvis....Resected margins are free from tumour,” the histopathology report concluded. While the surgeon was confident he had excised all the at-risk tissues, my mother was offered chemotherapy as a precaution.

After completing the cycles of carboplatin and gemcitabine chemotherapy, the CT scan radiologist reported on Jan 10, 2013 a “lymph node consistent with metastatic node. This is a new finding.”

A presumably stronger regime of chemotherapy involving taxol was given and once again the CT scan three months later showed the lymph node had grown.

A third concoction of chemo was administered (taxol and ifosfamide for four months).

Half way through, the oncologist prepared us for the worst, saying that if this chemo failed, then she could only offer hope to slow disease progression with future treatments.

Cure would be out of the question and future chemo would involve experimental drugs which the patient could import personally with the right paperwork.

I decided to check out the treatment at a clinic in Bangsar. I had no idea they offered immunotherapy, having heard only vague accounts through a friend that they had an alternate cancer treatment.

I went there (without my mother because I didn’t want to overload her with too much information), with an open mind and very inquisitive. I learnt that they offered P53 gene therapy and HITV.

I asked for scientific literature and explanation. While literature was skimpy the scientific explanation resonated with me and I also liked the idea that they did not entail serious side effects because they did not involve drugs.

Subsequently, a clinical response paper involving 167 patients was published in October 2013.

This paper showed very good success. It, however, did not influence our decision because it was published after my mother underwent HITV.

Getting back to the treatment time line, I decided (and my mother agreed) to try P53 mid-way through her third concoction of chemo. This was disclosed to the chemo oncologist.

The Bangsar clinic was quite upfront about the probability of success, or the lack of it. The post-chemo imaging report CT scan (PET scan this time) revealed that the “hypermetabolic left para-aortic nodal mass has increased in size. Neither chemo nor P53 worked.

We then abandoned further chemo, although the paperwork for the experimental drug was in order. In short, HITV commenced about a year after chemo was started.

The first PET CT, about three months after HITV treatment, reported: “The left para-aortic hypermetabolic nodes are gone, but there are other mildly hypermetabolic lesions situated more cranially and laterally” showed complete remission. As you rightly alluded in your letter, this is no proof that immunotherapy worked, given that high dose radiotherapy was administered.PET CT were done at three-month intervals, subsequently relaxed to six-month intervals. I’m happy to say that all these scans did not detect any cancer tumours. The latest scan is 38 months after HITV treatment.

Now, please recall how aggressive this cancer was – a new tumour in the para-aortic lymph node swelled it to 2.5 x 2cm in a span of about five months.

Take note also that HITV involves intratumoral injection of immature dendritic cells, a process that risks seeding tissues adjacent to the injection pathway with cancer cells.

By logical deduction, the radiotherapy part of HITV cannot have provided the systemic protection required to keep the patient free of any new tumours for 38 months, especially in the context of the aggressiveness of this cancer (my opinion).

Whereas the activated immune system could and probably did. To be clear, she received no cancer treatment other than HITV during this period.

Lastly, while clinical trial is a gold standard to aim for, you probably also know that it is very costly and a long journey. Meanwhile, the clock ticks for many cancer sufferers.

Just as my mother was allowed to import an experimental chemo drug, so too should patients have the option of HITV. I have certainly received more information on HITV than on the experimental chemo drug we were offered.

I believe doctors are taught the principle primum non nocere (Latin for first, do no harm). On this score, HITV does well with minimal side effects. One cannot say the same for the experimental chemo drug we were offered or FDA-approved immunotherapy drugs such as keytruda.

HITV was honed to its present state over decades by Dr Kenichiro Hasumi in Japan. Evidently America has cottoned on to this idea; former President Barack Obama launched the Moonshot 2020 programme last year to find “vaccine-based immunotherapies” against cancer! Wow, Obama was so specific when there are so many different approaches in immunotherapy.

Some background on me. I come from a family with strong history of cancer. My brother succumbed to colon cancer at only 32.

I would like to think that his premature death has a purpose for it spurred the rest of the family to do regular colonoscopy.

Several years later, we all went for genetic testing which revealed I have the HNPCC gene mutation.

With that, I undergo colonoscopy annually (for the past 20 years), and latterly annual ultrasound and biennial MRI as well.

These efforts paid off when I discovered a colon tumour (1997 at age of 38) and bladder tumour (2016) in very early stages and dealt with them successfully.

GAN TEE JIN

Kuala Lumpur

http://www.thestar.com.my/opinion/letters/2017/03/10/keeping-an-open-mind-on-unproven-treatments/

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Letters

Thursday, 16 March 2017

Cancer patients deserve better

 

WE would like to thank Gan Tee Jin for the letter “Keeping an open mind on unproven treatments” (The Star, March 10). We appreciate the effort to describe his family’s experience with HITV (Hasumi Immuno-Therapeutic Vaccine) and are glad that his mother has had a successful outcome after her treatment.

His mother is a living testimony that cancer is not always a death sentence, which sadly is an all too common perception among Malaysians.

We welcome feedback to our previous letter, “Clarifying immunotherapy” (The Star, March 3), and are keen to explain our position regarding oncology and evidence-based medicine.

The Malaysian Oncological Society (MOS) regards educating the public on cancer as one of our primary objectives and we strongly believe that the practice of oncology should be based on the best scientific evidence.

Gan’s letter raises several interesting points that continue to be debated in medicine, and science in general. Firstly, what kind of evidence is required to “prove” that something works? Is one successful case sufficient proof? Can we rely on our own, often flawed, observations to form judgements?

Work by Daniel Kahneman and Amos Tversky, recipients of the Nobel Prize in Economics in 2002, showed that men and women are inherently predisposed to errors in thinking. Mistakes due to errors in judgement have led to the tragedies caused by thalidomide and eugenics.

Medicine has wrestled with this problem for decades and thus evidence-based medicine was developed as a solution. Under this method, a new treatment is required to show strong evidence that it is effective before it is accepted by the medical community as valid.

Evidence should come from well-planned research, the observations meticulously recorded and audited independently and the results then analyzed, discussed and often debated and criticized to ensure its validity. This process is a component of evidence-based medicine and forms the foundation of modern oncology.

Another very interesting point is whether we can decide on a course of action if the scientific explanation makes sense. Thomas Huxley famously said that the great tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.

Unfortunately, the history of medicine is littered with the corpses of beautiful hypotheses that turned out to be wrong or even harmful.

Angiogenesis (the formation of blood vessels to feed the cancer) was shown to be vital in the growth of cancer cells. Drugs to stop or suppress this process were shown to be highly effective in stage 4 kidney and colon cancers.

Previously, oncologists believed that it should be even more effective in earlier stage cancers as the metastatic cancer cells have not had a chance to grow or spread. However, clinical trials involving thousands of patients and doctors across multiple cancer centres did not show any benefit in adding these drugs to standard treatment.

If we had treated patients based on scientific theory that sounded reasonable without strong supportive evidence then our patients would have received ineffective therapy and be burdened with the high costs of treatment and potential side-effects. Is this acceptable to the public?

Dr Kenichiro Hasumi’s paper published in the journal Oncoimmunology in 2013 was mentioned in the letter. This paper described their experience with HITV in 167 patients with advanced cancer.

Patients received intra-tumoural injections of dendritic cells followed by high dose radiotherapy and activated T cell infusions. In patients who were treated according to their protocol, i.e. less than 5 metastases and each less than 3 cm, the clinical response rate at 1 year was 75.7%.

Fairly impressive results but this only applies to 37 out of 167 patients in the case series. Was the PETCT assessments audited by an independent external party to confirm its accuracy?

The remaining 130 patients with more extensive disease had clinical response rates of 7-13% with HITV. This is slightly better than placebo.

Are these results sufficient to be regarded as successful? If so, that is a fairly low bar. Small metastases in a limited number of sites are known as oligo-metastases. These oligo-metastases can be treated with surgery, radiofrequency ablation or high dose radiotherapy with local control rates of 70-90%.

If good response rates can be achieved with such therapies then how much can we say is due to HITV? If further distant metastases do not appear after effective local treatment in oligo-metastatic disease then we should consider the possibility that there were no metastases in other distant organs to begin with.

Therefore, the absence of relapse after high dose radiotherapy of a local recurrence in one patient is not evidence of the effectiveness of HITV.

Only a randomized clinical trial can help to answer these questions. Yes, it is costly and time consuming but it can be done. Malaysian oncologists have been participating in a clinical trial to test a virus specific T cell immunotherapy for metastatic nasopharyngeal cancer developed by a Singaporean biotechnology company. If we insist on this kind of evidence from drug companies, why should we settle for anything less from others?

The former US president Barack Obama launched the Cancer Moonshot in January 2016 with the aim of accelerating cancer research to achieve the goal of making a decade’s worth of cancer research progress in five years.

Prior to Obama’s initiative, a joint program called the Cancer Moonshot 2020 was launched by private companies and academic cancer centres aimed at developing vaccine-based immunotherapy to combat cancer. These are exciting times for oncology and we look forward to the results from their meticulous research.

We are grateful for Gan’s letter as the various thoughtful points he raised gave us the opportunity to discuss the issues we grapple with daily. The Malaysian Oncological Society is committed to insisting on the best scientific evidence to guide medical practice. Our patients have entrusted us with their lives. They deserve nothing less.

DR MUHAMMAD AZRIF

Honorary Secretary

The Malaysian Oncological Society

http://www.thestar.com.my/opinion/letters/2017/03/16/cancer-patients-deserve-better/

HITV - New Cancer Treatment

Sunday October 23, 2011

Anti-cancer application

A Japanese physician and researcher has based his cancer treatment protocol on dendritic cells’ ability to enable selective and effective attack against tumour cells by the body’s own T cells.

SINCE the discovery of dendritic cells by Dr Ralph Steinman in 1973, much research has been carried out to elucidate the basic functional mechanism of dendritic cells.

Many medical research institutes and universities have conducted research in the use of dendritic cells in anti-cancer immunotherapy.

The ability of dendritic cells to enable selective and effective attack against tumour cells by T cells gave rise to great hopes that it would be an ideal cancer treatment.

Dr Hasumi is the man behind
the Human Initiated Therapeutic 
Vaccine therapy.

HITV (Human Initiated Therapeutic Vaccine) therapy was developed by Japan’s Dr Kenichiro Hasumi. He is a researcher physician, specialising in cancer immunotherapy. He has been involved in cancer immunotherapy research for more than 40 years.

His current protocol involves intra-tumoural injection (injecting directly into the tumour) of immature autologous (from the patient’s own body) dendritic cells in combination with tomotherapy (a type of radiation therapy).

Since 2008, over 360 late stage cancer patients have received this therapy in his Tokyo clinic and a remarkably high complete/partial recovery rate has been noted. His most recent results involving 26 patients with advanced treatment refractory cancer were published in the April edition of the journal, Cancers.

In summary, he has shown that combining immunotherapy with radiation therapy successfully eliminated metastatic and recurrent tumours on initial treatment in 21 of the 26 patients, with 13 of the 26 having no evidence of recurrent disease when evaluated by CT scans at various intervals of follow-up.

The overall disease-free period of the responding patients at the current time stands at about a year.

New strategies for cancer treatment

There are currently a few new directions that are being pursued in cancer therapy. They include:

Strategy 1: Remove the tumour’s mask. Cancer cells hide within normal structures like blood vessels. In order to conceal themselves, cancer cells rely on proteins from nearby healthy cells to hide their malignant proteins. New agents such as engineered peptide antibodies are increasingly able to strip away these disguises, exposing the tumours.

Strategy 2: Make the tumour less productive. Cancer cells actively pump out factors called immune system suppressors that wave off immune sentries and mislead them into thinking that the tumours are normal, healthy cells.

New compounds currently being tested can suppress the suppressors. Cancers are also rich in suppressor T cells, which direct the natural killer cells not to attack the cancer cells, resulting in immune tolerance. Drugs and radiation can wipe out these suppressor T cells and break the immune tolerance.

Strategy 3: Stack the immune system’s deck. The body’s T cells, which target invaders, may not be able to recognise the cancer cells. However, it is now possible to take from a patient some mononuclear cells and induce them to differentiate into immature dendritic cells (or antigen presenting cells).

When mixed with cancer cells, the dendritic cells will identify the cancer cell proteins and pass the information to cytotoxic T lymphocytes (natural killer T cells), thereby training the infantry T cells to spot the bad guys. The killer T cell population can also be enhanced in the lab and then injected back into the body.

Strategy 4: Build the right immune cells. Another way to sensitise T cells to detect cancer cells is to redesign them for the job. Scientists do this by extracting the cells, genetically modifying them to recognise tell-tale cancer proteins, and then using these supercells to treat the patient.

The HITV protocol

Dr Hasumi’s HITV protocol is basically Strategies 2 and 3 in combination with conventional radiotherapy.

This patient-specific induced therapeutic cancer vaccine is believed to be effective in killing off microscopic and tiny nests of cancer cells, thereby preventing any future cancer recurrence.

There are three essential steps:

1. Firstly, the intra-tumoural injection of immature dendritic cells, followed by infusion of cytokine induced natural killer cells results in millions of cytotoxic T cells which have been trained to zero in on the cancer cells.

The direct injection of immature dendritic cells into the tumour allows for adequate numbers of dendritic cells to reach the tumour site. The dendritic cells also have the benefit of an ideal in vivo environment in the patient’s body and there is less chance of antigenic difference.

2. This is followed by radiotherapy a week later, which causes further DNA damage, protein damage and apoptosis of the cancer cells, resulting in debulking of the tumour.

Radiotherapy also wipes out the regulatory T cells, thereby helping to break up the cancer’s immune tolerance.

Combination with radiotherapy achieves two goals – damaging the cancer cells to kill them and to expose their DNA and proteins, and wiping out the regulatory T cells within the tumours.

3. A second intra-tumoural injection of immature dendritic cells, followed by cytotoxic T cells infusion, allows the immune system to mop up all remaining cancer cells, including those which could have undergone transformation or mutation.

This second round of HITV treatment aims to wipe out newly mutated cancer cells.

HITV therapy has been found to be highly effective in the following patient conditions:

1. Solid tumours
HITV is applicable for any type of solid cancers and any stage. However it is not suitable for haematopoietic cancers such as leukaemia.

2. Tumours are localised in treatable sites
As intra-tumoural injection of dendritic cells is the hallmark of HITV, it is important that the tumour is located in sites which are accessible by needle.

3. Tumour size of less than 3cm in diameter
This limitation is due to the standard beam diameter of tomotherapy, which is 3cm. Dendritic cell vaccine is also ineffective when injected into the necrotic centre of large tumours.

4. Less than five metastatic tumour lesions
Again, the limitation is due to the adverse reactions to radiotherapy that may occur when multiple sites have to be treated in one sitting. However, Dr Hasumi has experience in treating up to 15 lesions in one go.

5. No pleural or ascitic effusion
Pleural and ascitic effusion are typical signs of extensive cancer dissemination and the chances of success in such cases is greatly diminished.

He’s in town
Dr Kenichiro Hasumi will be in Kuala Lumpur on Oct 24 to deliver a lecture entitled “Breakthrough in Cancer Treatment – The Cure to Cancer Is Now In Malaysia”. The lecture will be held at the Le Meridien Hotel, Kuala Lumpur, at 7.30pm. For enquiries, call 03 7784 6686.

http://thestar.com.my/health/story.asp?file=/2011/10/23/health/9730370&sec=health

HITV Therapy: Cancer cure is now in Malaysia

Bernama

Monday, October 24th, 2011 23:24:00

KUALA LUMPUR: There is a new hope for cancer patients in Malaysia.

A vaccine widely known for treating late-stage cancer -- almost all types of cancer, except leukemia -- is now available in the country.

The Human Initiated Therapeutic Vaccine (HITV), which was only available in Japan previously, is able to completely destroy microscopic and tiny nests of cancer cells, thus preventing any future recurrences.

Discovered in 2005 by Dr Kenichiro Hasumi, a Japanese physician and researcher, HITV is an autologus (patient derived) active cell-based immunotherapy for metastatic or late-stage cancer patients.

It is based on immunology that harnesses human immune system's innate and adaptive ability to combat diseases.

Dr Hasumi, founder and chairman of Hasumi International Research Foundation in the United States, has dedicated more than 40 years of his life to find a cure to cancer.

Speaking at a media conference today, Dr Hasumi said the therapy was highly effective for patients suffering from late-stage cancer, when used in combination with radiotherapy.

"The use of tomotherapy (a type of radiation therapy) is important in this protocol. It can target the tumors precisely in one sweep, while reducing the radiation exposure to the surrounding tissues," he said.

The treatment includes harvesting immune cells from the patient, culturing them in the laboratory to become immature dentritic cells, and then re-introducing them into the patient's body, through injection into the tumor.

HITV course takes about three weeks, with 10 days of actual treatment. Patients will have to be examined with PET-CT scan after the treatment periodically, to monitor the tumors for regression.

While the treatment was only available in Japan, nine Malaysians suffering late stage of various types of cancer have decided to give it a try. Five of them have shown complete response.

They include Goh Sai Wah, 58, a non-smoker who was diagnosed with stage four lung cancer with extensive spread to the spine and bone in May, last year.

She underwent the HITV therapy in Japan on Oct 30, last year and in her follow-up check, six weeks later, almost all cancer cells had disappeared.

Now, 365 days later, and counting, she is very much alive and well.

Dr Hasumi said, since late stage cancer was a very difficult stage to cure, he hoped that in future, there would be innovations to cure cancer in the early stages.

HITV therapy costs about RM200,000, if patients decide to have it in Japan.

In Malaysia, it will cost about RM150,000.

The therapy is now available at the Mahameru International Medical Centre but medical practitioners are trying their very best to introduce HITV to all hospitals in the Klang Valley, in an effort to give late-stage cancer patients a new hope in life.


http://www.mmail.com.my/content/85014-hitv-therapy-cancer-cure-now-malaysia