The New Legalist editor’s note:
Modern Western medicine (MWM) and traditional Chinese medicine (TCM) are based on two sharply different philosophical worldviews. To help unleash and bring into play, but not to "harness", the self-healing capability of human immune system in treating diseases has been the core idea of TCM ever since antiquity. MWM, by attaching some importance to the power of the immune system in fighting cancer, is starting to speak a language similar to that of TCM. Still, this report betrays two fundamental differences between the two medical systems with philosophical implications:
A) MWM adopts a confrontational attidude towards the human body ("harnessing") while TCM a non-confrontational Daoist pushing-the-boat-along-with-the-current approach. All the rich variety of therapeutic methods in TCM, such as herbal medication, acupuncture and moxibustion, cupping, scraping, and stretching and patting are meant to help release and facilitate, not to manipulate or harness, the self-healing power of the immune system inside the body (by dredging the meridian channels or restoring Yin-Yang balance).
B) MWM depends on an atomistic view of the bodily functioning, as this report typically shows, looking at the organs as mechanical mixtures of ever divisible elements in disregard of the physical conditions of the whole body (or not seeing the wood for the trees), whereas a competant TCM therapist, what ever method he/she uses, always maintains a holistic view of the whole body system when attending to the parts and details of the specific organs. Or, while MWM, as the Chinese saying goes, "attends to the head if the head aches and to the foot when the foot hurts", TCM therapies may do someting on the foot to treat symptoms in the head or vice versa. In authentic TCM (not today’s Westernized “Chinese medicine”), all cancerous growths, wherever located in the body, are but symptoms of one ailment, that is, meridian obstruction, and the way to cure it is to dredge the related channel(s) by applying a therapeutic method that is best suited to the WHOLE physical conditions of the patient. (This editor personally witnessed a close friend of his reducing into nil a tumor (the size of a table tennis ball) on the outer side of her leg just by repeatedly patting the gall bladder meridian for a period of time.) And TCM herbal medication never breaks down the herbs into separate chemical components and single out some of them for therapeutic use but on the contrary almost always combine different whole herbs into one prescription to maintain and achieve holistic balance between the different qualities inherent in the different components and differnt kinds of herbs to prevent harmful side effects.
In a word, striving for holistic balance and harmony, instead of fragmentation and confrontation, is the key in TCM for a more effective and economical but less painful way leading to better health.
(By the way, this same approach is also the secret in traditional Chinese statecraft which nurtured and sustained the Chinese civilization, which prospered continuously for thousands of years long and remains the only surviving ancient civilization on this planet. That is because traditional Chinese medicine and politics shared the same philosophical worldview. Hence the old Chinese saying: "The one ’medical’ system of thought puts the state in order on the upper level, conducts the person on the middle level, and cures diseases on the lowest." 上医治国，中医治人，下医治病。)
The notion that the human immune system can be enlisted to fight cancer has a long history in medical science, dating back to the beginning of the 20th century. For much of that period, researchers sought ways of strengthening the natural immune response to cancer through the development of therapeutic cancer vaccines and other immune-stimulatory techniques.
As this work was under way, a smaller group of scientists focused on the means by which cancer cells protect themselves from an immune system attack. This latter approach gained momentum in the 1990s, with discoveries about the function of T cell co-receptors in regulating the immune response to disease. It had previously been thought that co-receptors played a purely stimulatory role, inciting T cells to mobilize an immune system assault on infected or malignant cells. Researchers later discovered that some co-receptors act as a brake on the immune response, protecting the body from autoimmune disease. This discovery suggested that blocking such inhibitory co-receptors with drug agents could unleash an immune system attack on tumor cells.
The discovery of PD-L1
In 2000, Dana-Farber Cancer Institute’s Gordon Freeman, PhD, and his colleagues published a study announcing the discovery of the protein PD-L1 (programmed cell death 1 ligand 1) on normal cells. The researchers found that PD-L1 exerts an inhibitory effect on T cells by binding to the T cell co-receptor PD-1, thereby signaling the T cell not to instigate an immune system attack.
A year later, Freeman and his colleagues published a follow-up study, reporting that PD-L1 appears not only on some normal cells but on certain cancer cells as well. The implication was that an agent that blocks PD-L1 (or a related ligand, PD-L2) could release the brakes on an immune system attack on the cancer. The discovery prompted pharmaceutical companies to pursue the development of drug agents that block PD-1, PD-L1, or PD-L2. Several of these drugs – known as immune checkpoint inhibitors – have recently received Food and Drug Administration (FDA) approval for treating certain types of cancer and are being tested in a variety of other cancers.
The discovery prompted pharmaceutical companies to pursue the development of drug agents that block pd-1, pd-l1, or pd-l2. The discovery of a cell protein reveals a new way of harnessing the power of the immune system to fight cancer. Immune checkpoint inhibitors are now showing promise against a wide variety of cancers.
Early results of clinical testing
Dana-Farber investigators are now studying which tumor types respond to immune checkpoint inhibitors, the mechanism by which such inhibitors work, and how they can be improved. In early-stage clinical trials, immune checkpoint inhibitors are producing striking results in some cancers. In a phase 1 trial led by Dana-Farber investigators Margaret Shipp, MD, and Phillippe Armand, MD, PhD, investigators tested the PD-1 blocker nivolumab in 23 patients with Hodgkin lymphoma who had exhausted numerous other treatment options, often including a stem-cell transplant. Some 87 percent of the participants had experienced a full or partial remission of the disease. The majority of them were still doing well a year and a half after treatment, when the results were published in the New England Journal of Medicine. The findings prompted the FDA to designate nivolumab a “breakthrough therapy” for relapsed Hodgkin lymphoma and a multinational phase 2 trial is now under way.
In glioblastoma, researchers led by Dana-Farber’s David Reardon, MD, and Gordon Freeman tested a PD-1-targeting antibody in mice with the cancer. More than half the mice that received the agent were long-term survivors, showing no evidence of tumor in their brain after 50 days. 25-30 percent of those that received antibodies against PD-L1 and CTLA-4 were considered cured. On the strength of these results, Dana-Farber investigators have opened three clinical trials of these agents.
In a phase 1 trial of a PD-L1 inhibitor in patients with bladder cancer, DanaFarber’s Joaquim Bellmunt, MD, PhD, and his colleagues reported that, after 12 weeks of treatment, there was tumor shrinkage in 52 percent of the patients whose T cells have high levels of PD-L1 prior to treatment. Although more than half of the participants experienced adverse side effects to the drug, known as MPDL3280A, none of them were particularly severe.
Investigators at the Dana-Farber/Brigham and Women’s Cancer Center led by Toni Choueiri, MD, opened their first clinical trial of a PD-1 and PD-L1 blocker for patients with kidney cancer five years ago. Although the results haven’t been published yet, about 20 percent of the trial participants, many with tumors that defied previous treatments, responded to the checkpoint inhibitor. Choueiri and Sabina Signoretti, MD, are analyzing tumor tissue for biological signs that indicate which patients are likely to respond best to the treatment.
Dana-Farber researcher Peter Hammerman, MD, PhD, and his associates are studying the genetics of lung cancer to determine if certain mutations render tumors more susceptible to immune checkpoint inhibitors. David Barbie, MD, is studying whether variations in the immune system from one person to another affect individuals’ cancer-fighting ability. The researchers also are exploring whether as-yet undiscovered checkpoint proteins play a role in turning off an immune system attack and could be targeted in future studies.
One of the hallmarks of immune checkpoint inhibitors has been the durability of the cancer remissions they produce unlike some chemotherapy and targeted agents that lose potency as cancer cells develop new genetic mutations.
On the strength of the results in early clinical trials, investigators plan to test immune checkpoint inhibitors against additional types of cancers. While these therapies are likely to be more effective against some malignancies than others, immune checkpoint blockade is rapidly becoming a fixture of the medical arsenal for cancer.
Ansell SM et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. N Engl J Med. 2014 Dec 6. [Epub ahead of print].
Akbay EA et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013 Dec;3(12):1355-63. doi: 10.1158/2159-8290.CD-13-0310. Epub 2013 Sep 27.
Omid Hamid, M.D et al. Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma. N Engl J Med 2013; 369:134-144 July 11, 2013 DOI: 10.1056/NEJMoa1305133. Suzanne L. Topalian, M.D.et al. Safety, Activity, and Immune Correlates of Anti– PD-1 Antibody in Cancer. N Engl J Med 2012; 366:2443-2454June 28, 2012DOI: 10.1056/NEJMoa1200690. Philippe Armand et al. Disabling Immune Tolerance by Programmed Death-1 Blockade With Pidilizumab After Autologous Hematopoietic Stem-Cell Transplantation for Diffuse Large B-Cell Lymphoma: Results of an International Phase II Trial. J Clin Oncol. 2013 Nov 20;31(33):4199-206. doi: 10.1200/JCO.2012.48.3685. Epub 2013 Oct 14.