Checkpoint Inhibitors at 120k a round: the limitations of conventional oncology’s “immunotherapy” research.

As the ASCO meeting last year finally concluded, (See our post on the ASCO meeting), immunotherapy is one of  the most scientifically exciting research fields, if only because it remains one of the most long term safe and efficient pathways to reverse cancer,  once the T cells have been restored and are able to store the malignancy surveillance memory. (1).

However, in conventional, allopathic drug-based oncology,  immunotherapy for cancer means developing expensive treatment drugs, usually for short periods  to harness artificially one’s immune system to fight the cancer. In this perspective, it has been estimated that conventional immunotherapies  could add upwards of 40 billion dollars to the pharmaceutical industry.

Scientists have been researching immunotherapy  for decades and some, like Beard and others, have been partially successful, using, among others, holistic techniques like heat, infections and viruses. But for the mainstream allopathic medical community, billions of dollars for research have not been very productive in terms of reducing the cancer incidence and survivability. Just recently though, the mainstream oncology research community has claimed to have found  new breakthroughs in this field of immunotherapy.  (2, 3)

 NEW “BREAK-THROUGHS” DRUGS TARGET THE IMMUNE SYSTEM

“Cancer immunotherapy is the most exciting thing we have going on in the field.” Dr Peter Bach, director of the Center for Health Policy and Outcomes at the Memorial Sloan Kettering Cancer Center in New York.

Via different pathways, cancer produces proteins to shield itself from the immune system surveillance and attack system.

Now, recently, big pharma drug scientists have found an artificial way around this obstacle, via what they call “checkpoint inhibitors”, which they claim is a “breakthrough”.  Checkpoint inhibitors are drugs that pull off cancer’s invisibility cloak by blocking the switch that turns it on.

“It prevents that invisibility cloak or that force field or shield … from going up,” Brahmer says, “so it can’t shield itself from the immune system.” says Dr. Julie Brahmer, an associate professor of oncology at John Hopkins. (2)

According to hte mainstream scientific media, these drugs seem to be working, at least in the short term and can target melanomas,  kidney cancer, bladder cancer, head and neck cancers, lymphoma, breast and lung cancers. (ibid.).

“Our study deals with the central problem in human cancer immunotherapy, which is how to effectively attack common epithelial cancers,” said Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research. “The method we have developed provides a blueprint for using immunotherapy to specifically attack sporadic or driver mutations, unique to a patient’s individual cancer.” (cf Ft 3).

All malignant tumors have genetic alterations, some of which can lead to the production of mutant proteins that are capable of triggering an antitumor immune response. Research led by Rosenberg and his colleagues had shown that human melanoma tumors often contain mutation-reactive immune cells called tumor-infiltrating lymphocytes, or TILs. The presence of these cells may help explain the effectiveness of adoptive cell therapy (ACT) and other forms of immunotherapy in the treatment of melanoma. (4)

ANECDOTAL EVIDENCE

One cancer patient, Ms Marder, after having endured a lung cancer recurrence, (5) volunteered for one of Brahmer’s studies testing a checkpoint inhibitor called nivolumab, or Opdivo, for lung cancer. (6) Within weeks of starting her infusions, the tumors in her left lung began to disappear. (Op. Cit, ft 2).

 In another study with another patient,  Rosenberg and his team set out to determine whether TILs from patients with metastatic gastrointestinal cancers could recognize patient-specific mutations. They analyzed TILs from a patient with bile duct cancer that had metastasized to the lung and liver and had not been responsive to standard chemotherapy. (7)

The researchers first did whole-exome sequencing, in which the protein-coding regions of DNA are analyzed to identify mutations that the patient’s immune cells might recognize. Further testing showed that some of the patient’s TILs recognized a mutation in a protein called ERBB2-interacting protein (ERBB2IP). The patient then underwent adoptive cell transfer of 42.4 billion TILs, approximately 25 percent of which were ERBB2IP mutation-reactive T lymphocytes, which are primarily responsible for activating other cells to aid cellular immunity, followed by treatment with four doses of the anticancer drug interleukin-2 to enhance T-cell proliferation and function.

Following transfer of the TILs, the patient’s metastatic lung and liver tumors stabilized. When the patient’s disease eventually progressed, after about 13 months, she was re-treated with ACT in which 95 percent of the transferred cells were mutation-reactive T cells, and she experienced tumor regression that was ongoing as of the last follow up (six months after the second T-cell infusion). These results provide evidence that a T-cell response against a mutant protein can be harnessed to mediate regression of a metastatic epithelial cell cancer.

“Given that a major hurdle for the success of immunotherapies for gastrointestinal and other cancers is the apparent low frequency of tumor-reactive T cells, the strategies reported here could be used to generate a T-cell adoptive cell therapy for patients with common cancers,” said Rosenberg.

LIMITATIONS OF CONVENTIONAL ONCOLOGY’S CLAIMS TO IMMUNOTHERAPY “BREAK-THROUGHS”

According to the manufacturers of the Checkpoint inhibitor drug  Livolumab  (made by Bristol-Myers Squibb) and other sources, checkpoint inhibitors can cause serious side effects when the immune system attacks healthy cells, causing dangerous, even sometimes life-threatening organ damage.  Even if these drugs are easier on the body than chemo, they are still synthetic drugs which do not work via the body’s synergy-based intelligence, even in combitions and which do not contribute much to a personalized and lifestyle approach.

Furthermore, nivolumab is typically combined with Yervoy (ipilimumab) and has been shown to lead to  tumor regression in only a third of patients who have advanced melanoma. (The response is shown to be quicker when the combination is used versus a single drug). In addition, we do not have much hindsight, once discontinued,  cancer may still come back. The ongoing clinical trials have not proven efficiency from this viewpoint, let alone the long term absence of serious complications and mutagenic resistance.

 At 120,000 dollars a round, (8) these “break-through” drugs are especially “break-through blockbusters” from the money viewpoint, for the benefit of the  conventional allopathic medical system and all the more so that the clinical trial infusion frequency   is two weeks.  That’s 240,000 dollars per month per person, money which could be better invested in prevention if we had a responsible Government and public health system.

In the investment world, analysts believe that in the next 5 years that the stock for Bristol Myers Squib could have a valuation increase greater than 25% thanks in part to the revenue per patient that this drug would create (See the checkpoint drug’s highlighted source above). With the baby-boomers tsunami coming up, drug profits are sure to increase.

Meanwhile, thousands of what the system calls “spontaneous remissions” of the most difficult malignancies have been reported in the scientific litterature. But most of  Big Pharma is not interested in finding out why these Nobel worthy holistic pathways work, because most of these cases have used holistic methods which do not generate billions of dollars.

Ch. J.

REFERENCES

(1).  T-cells  normally remember how to attack the tumor and stop the cancer from putting up a shield, see our other posts on this question.

(2). Tran et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. May 9, 2014.   Source

(3).  NPR. Source

(4). In ACT, a patient’s own TILs are collected, and those with the best antitumor activity are grown in the laboratory to produce large populations that are infused into the patient. However, prior to this work it had not been clear whether the human immune system could mount an effective response against mutant proteins produced by epithelial cell cancers. These cells comprise more than 80 percent of all cancers. It was also not known whether such a response could be used to develop personalized immunotherapies for these cancers.

(5). When Barbara Marder, 73 years old, was diagnosed with lung cancer three years ago, she had part of her right lung removed, went through a round of chemotherapy and tried to move on with her life. But a routine scan a year later found that he cancer came back, as they usually do,  this time in her other lung.

(6).  The description for nivolumab indicates that it is a human igG4 antibody blocking the programmed cell death-1 receptor. For its clinical and pharmacokinetic data, see the highlighted word nivolumab above.

(7). The patient, a 43-year-old woman, was enrolled in an NIH trial of ACT for patients with gastrointestinal cancers (Clinical trial number NCT01174121).

(8). In the US. In other countries, the prices is less.  According to England’s National Institute for Health and Care Excellence (NICE) the price is £15,000 per 40-mL vial. A 40mL vial contains 200mg of Yervoy (the checkpoint inhibitor), with is sufficient for a single dose for a 67kg (145lb) person. Typical treatment is four doses administered over 12 weeks. Thus the cost in Britain is £60,000, which is $91,400. http://www.nice.org.uk/news/pr…  And it has been reported that other countries pay even less. One reason other countries don’t have as high a cost is that they refuse to pay what is charged.  In the US,  drug companies lobby (aka bribe) politicians to allow them to charge what they want and then they spend more than their R+D costs on marketing the drugs to the people who can prescribe them.

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