Off-label Drugs and its potential use against cancer – An Intro by Raymond Chang MD

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The off-label use of a drug is the prescription or taking of a medicine for other than what it was originally intended for as described or approved by the US FDA or similar regulatory body. Simply put, medication usage for what is not on the official label of the drug is “Off-Label”.

Although hardly uncommon, there are distinct reasons why off-label prescribing is not as common as it ought to be if based on scientific evidence of efficacy alone. Firstly, it is unlawful to market, advertise or promote the off-label use of drugs (See an example of the intricacies and complexities as well as the conundrum of off-label regulation by FDA, US Congress and the Courts as evidenced by the recent saga of the Neurontin case in this 2004 paper by Robert Kaufman of the Harvard Law School).

Secondly, the insurance industry frequently invoke the off-label nature of a prescription to decline payment (ie they will not pay if they can find a reason not to pay, why would they? See illustrative story here), although Medicare in recently expanded its coverage of off-label treatments for cancer (See related news here), although it mainly applies to the use of an agent already approved for the coverage of some form of cancer to be covered when used for a different cancer, which is quite different from the drugs presented here ( approved for some other condition than cancer, to be applied for use as an anti-cancer), ie it is off-label use of a cancer drug rather than off-label use of a drug for cancer.

Finally, although the FDA does not regulate the individual physician’s prescription of a drug as long as it has been approved,  the legal liability for the physician is deemed higher especially if harm arises out of the course of its use and if it seems to deviate from “standards of care” which is how physicians are legally judged. Furthermore, physicians may be deemed to be engaged in human experimentation when prescribing drugs off-label (See a balanced discussion by Maxwell Mehlman JD on the legality and bioethics issues of off-label prescribing here)

It is because of potential legal risk on the part of the prescribing physician, limitations of insurance reimbursement, as well as the lack of knowledge about the potential off-label usefulness that limits the broader use of such drugs.  The unlawfulness of pharma related marketing or promotion and their lack of interest in investing in new clinical trials to demonstrate new indications when a drug has already gained FDA approval is often a factor limiting the broader use off-label treatments.

Back to the cancer patient: my purpose here is just to broaden the awareness of the science behind the usefulness of some very common and some not so common drugs that could jointly or otherwise enhance a patient chances of overcoming cancer, and to disentangle the healing process from insurance red-tapes and legal suffocation (See Disclaimer).

More useful info on Off-label Drugs for cancer can be found at the NCI site here.

TOPICS in this blog include:

Introduction to Off-label drugs for cancer

Posts (Publisjed, Most Recent or Recently Updated First)

  1. Statins, pleiotropic anti-cancer (6.10)
  2. Gamma-delta immunotherapy (2.09, updated 6.10)
  3. Urso as chemopreventative (5.09)
  4. Noscapine  near perfect (5.09)
  5. Naltrexone (2.09)
  6. Bisphosphonate (2.09)
  7. Clodronate for breast cancer (2.09)
  8. Gossypol (11.08)
  9. Metformin (10.08)
  10. Disulfirim (11.08)
  11. Dipyridamole (11.08)
  12. Cimetidine (11.08)

Draft Topics (To Be Published)

  • Cox-2 inhibitors (e.g. Celecoxib i.e. Celebrex)
  • PPAR agonists
  • Heparin
  • Anti-coagulants
  • Coumadin
  • Tetracyclines as Anti-angiogenics
  • Clarithromycin against lung cancer
  • Artesunate and Antimalarials for cancer
  • Lithium as immunomodulator
  • Anti-depressants against cancer
  • Cannabinoids
  • Benzodiazepines
  • Theophylline for B cell leukemia (CLL) / lymphoma (NHL)
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Antimalarial Artesunate’s potential against cancer

February 4, 2011 1 comment

Artemisinin or Qinghaosu (青蒿素), derived from the leafy portions of the sweet wormwood plant Artemisia annua L. or qinghao (青蒿), and isolated in 1972 by Chinese chemists, is a potent anti-malarial that has revolutionized modern malaria treatment.  What makes this and related bioactive derivatives super interesting is that they exhibit potent anticancer effects in a variety of human cancers (Expert Rev Mol Med. 2009 Oct 30;11:e32), a fact which has been known for almost three decades but relatively unexplored.

In Vitro and in Vivo Research

One of the most notable semi-synthetic derivative drug from artemisin is artesunate (ART), which was developed for malaria in the 1980’s was noted to have anti-cancer activity along with other artemisinins by the early 1990’s (J Nat Prod. 1993 Jun;56(6):849-56), with Lai and Singh reporting that artemisinin selectively killed MOLT-4 lymphoblastoid leukemia cells in 1995 (Cancer Lett 1995; 91:41-46). Subsequent research by Thomas Efferth’s team in Germany demonstrated artesunate’s in vitro efficacy against multiple tumor lines (Int J Oncol. 2001, 1:767-773) and was most active in vitro against leukemia and colon cancer while modestly effective against melanomas, breast cancer, ovarian cancer, prostate cancer, glioma, and renal cancer. The same research team was also responsible for elucidating much of the molecular mechanisms of efficacy of ART against cancer, which included direct cytotoxicity, anti-angiogenesis as well as induction of apoptosis (See Drug Resist Updat. 2005 Feb-Apr;8(1-2):85-97).

Clinical Studies

Beyond the test-tube, it has been found that ART (as well as artemisinin and other artemisinin derivatives) can successfully treat grafted human tumors in laboratory animals (Biochem Pharmacol 2004 Dec 15;68(12):2359-66), and this lead to Efferth’s group to attempt to treat two uveal melanoma patients after chemotherapy has failed.  Generally, such cases have a median survival of 2-5 months, but with ART treatment, one patient went on to live 24 months and the other patient is alive at 47 months (as of 2007) after initial diagnosis of stage IV melanoma. Other clinical reports include the successful use of artemether, a related compound, in the treatment of a pituitary macroadenoma (Integr Cancer Ther. 2006 Dec;5(4):391-4) and a report of a 72 year old gentleman in India with laryngeal squamous cell cancer, which responded nicely to ART alone with a 70% shrinkage over 2 months (Arch Oncol 2002; 10(4):279-80).  In China, a clinical trial comparing ART + chemo vs. chemo alone against non-small cell lung cancer found a modest improvement of the time to progression in ART treated patients (Zhong Xi Yi Jie He Xue Bao. 2008 Feb;6(2):134-8) despite the fact that lung cancer is one of the least sensitive cell lines to ART when tested in vitro.  Anecdotally, dogs with bone cancer and lymphosarcoma have been reported to rapidly respond to artemisinin, and patients with prostate cancer, brain tumors, pancreas cancer, breast cancer were also anecdotally reported to have been helped by artemisin derivatives. Reportedly, Dr. N. Singh from the U. of Washington mentioned the case of a man with brain cancer who has been in coma for 5 months who came out of the coma after 21 days injections of artemether, a related compound.  (See newsletter article by Christina White, “Cancer Smart Bomb, Part I & II: An Idea from Ancient Chinese Medicine”, New Horizons, Summer & Fall 2002 issues published by the Brewer Science Library -> an online excerpt is available).

In Germany, a trial of ART against breast cancer is currently recruiting at the University of Heidelberg and there was also a phase I trial in the U.K. against colon cancer that was completed but unpublished.

ART availability

ART is largely non-toxic, with related compounds having been administered to over 2 million patients, children and adult, world-wide without significant concern for serious adverse effects reported (Trans R Soc Trop Med Hyg. 1994: 88 (Suppl 1):S3-4.) and ART is cheap compared to conventional cancer drugs, but then why aren’t there more trials or more wide-spread use of ART as an off-label cancer treatment?  The usual combination of ignorance (most conventional oncologists I have spoken with not even unaware of artemisia or artemisinin or ART’s potential against cancer, and some have never heard of a drug called artesunate) and commercial interests (or lack of interest rather) are the culprits here hampering an advance. Furthermore, in the specific case of ART, its highly restricted availability is also contributory (believe it or not, in the USA, it was only in 2007 that the FDA approved investigational new drug (IND) protocol # 76,725 for the use of artesunate in treating “severe malaria”, making it the first time that any of the artemisinins are legally available as a drug in the US.  Currently, the US army (Walter Reed Army Institute of Research) supplies ART to the Center of Disease Control (CDC) which is in turn the only legitimate source of the drug in the US, and even then, it is only available to hospitals, upon request and on an emergency basis, by the CDC ! (See CDC website for  ART availability details).  Worldwide, genuine oral ART is also difficult to obtain due to WHO concerns and constraints secondary to surging malaria resistance to one of the last remaining effective anti-malarials, compounded by a problem of rampant distribution of fake ART in third world countries.

My take

Despite some concern for neurotoxicity based on animal studies, ART and related compounds are some of the least toxic medications on the market for any condition, without clinically relevant toxicity after extensive oral and parenteral use in various populations for the past two decades, except for sporadic and transient cardiac dysrhythmias.  These compounds are also relatively inexpensive, being dispensed mainly in the third world in poor populations where malaria is endemic.  With the demonstrated bioactivity in the laboratory and the promising anecdotal cases, these seem to be perfect compounds to try against cancers , either in combination or when other treatments fail. It is hoped that regulatory authorities could loosen the grip on dispensing of ART and related medicines, especially where malaria or malaria resistance is not a concern in the territory (e.g. in the US or Western Europe, Japan) to allow cancer patients a compassionate avenue to the treatment especially when other treatments have failed.

My research group at the Institute of East West Medicine here in New York have noticed the potential of anti-malarials against cancer in general and we are currently exploring other naturally derived anti-malarials as possible anti-cancer agents with generous support from the Gray Charitable Trust and other private supporters.  Funding permitting, semi-synthetic and synthetic derivatives of artemisinins could also be systematically explored and developed with a use against cancer in mind, and combinations of ART with other anti-cancer agents to achieve synergies should also be urgently investigated.

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Anti-HIV’s now also anti-cancer ?

Its been a while since I last updated here, and there are many potential off-label drugs for cancer that should be NEXT written about, but one category that deserves immediate attention are the anti-HIV drugs.  One of them, Nelfinavir, was even called “a magic bullet to annihiltate cancer cells” recently (Cancer Biol Ther. 2009 Feb;8(3):233-5).

Of course, cell signalling pathways as a source for new target therapy drugs against cancer is all the rage now but to develop a new candidate molecule into an approved drug can cost a billion dollars and take over 10 years, so how about looking at established targeted therapies for other diseases such as HIV and see if there are potential off-label drug candidates for cancer there ?  Well, Dr. Phillip Dennis and colleagues did exactly that:  they took existing HIV protease inhibitor drugs and tested 6 of them against cancer cell lines derived from 9 different human tumor types and found that three of the drugs (ritonavir, nelfinavir and saquinavir) reduced the growth of 60 of those cell lines. In the laboratory, nelfinavir or Viracept®, a first generation speific protease inhibitor designed for HIV appeared most potent (Autophagy 4(1):107-9, 2008).

Nelfinavir seems to exercise a broad-spectrum cancer killing effect through multiple pathways: apoptosis, necrosis and autophagy (See Clin Cancer Res 13(17): 5183-94, 2oo7), and is also noted to have antiangiogenic and immunomodulatory ability.  Nelfinavir has also been shown to have radiosensitizing properties (Cancer Res. 2005 Sep 15;65(18):8256-65.) via Akt activation making it a logical addition to radiation therapy and trials using it in this fashion are underway against brain, rectal and pancreas cancers.  One of the ways it works with chemo and radiation may be via disruption of the process by which hypoxia occurs by restoring proper blood flows to tumors ad making them more vulnerable to other therapies according to research by McKenna of Oxford. McKenna’s group also demonstrated as early as 2005 that Nelfinavir radiosensitized cancer cells and a small trial he conducted with nelfinavir + chemoradiation showed dramatically that 6 out of 10 patients with advanced pancreas cancer had their cancer shrank enough to be surgically removed whereas normally it would be only 1 in 10 (J Clin Oncol. 2008 Jun 1;26(16):2699-706) .

Using anti-HIV drugs against cancer is not a novel idea, the grand daddy anti-HIV drug AZT was originally tested against cancer in the ’90s because of laboratory promise, but it did not pan out in human testing.  HIV patients are at increased risk for certain cancers, and those on protease inhibitor treatment have been thought to have reduced kaposi’s sarcomas and lymphomas, this observation was noted early on and trials to test the drugs against HIV related cancers were planned as early on as 2003 in Italy (Lancet Oncol. 2003 Sep;4(9):537-47)

The anti-HIV protease inhibitors have been around since 1993 and their dosage, safety and toxicity in humans are well known.  Currently, multiple phase 1/2 studies are under way to evaluate the potential of nelfinavir in renal cell, rectal, lung, adenocystic, liposarcoma, brain and pancreas cancers, alone, and in combination with chemotherapy and radiotherapy and other targeted agents such as bortezomib or Velcade® and temsirolimus or Torisel®. (See current US trials here)

The usual starting dose for nelfinavir is 1250 mg twice a day (costs about $25/day in the US) but ongoing phase 1/2 trials are testing higher doses.  Its common side-effect is diarrhea, blood lipid abnormalities  (good reason to add a statin as another off-label anti-cancer treatment, see here; but caution must be exercised when adding or selecting a statin due to potential drug-drug interaction via the CYP pathway where the lactone pro-drugs simvastatin and lovastatin should not be used, see here) and redistribution of body fat (64% at 13 months of usage), as well as glucose intolerance (with a diabetes risk of 3% with long-term use) but its side-effects do not overlap with mainstream anti-cancer agents’ and is usually tolerable for long term treatment.

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Urso as Chemopreventative

Off-label therapeutic inspirations sometimes come from my patients.

And this one came from Noreen T.  Noreen has advanced metastatic breast cancer refractory to almost all treatments and has just started on an investigational Dendritic vaccine + Zadaxin (thymosin) but her disease is progressing rapidly with rising markers and an obstructive jaundice caused by liver metastases.  External drainage and internal stenting was out of the question and she was offered lactulose as we need to buy time for the immune treatments to work.  In my searches, I came across Ursodiol (Urso) which I am familiar with in its use in preventing gallstones or for primary biliary cirrhosis and other cholestatic conditions.  Its just that its not usually used in oncology.  Researching deeper led to the interesting discovery for me that it is also an anti-cancer (which I doubt that most my hepatology or GI colleagues are aware). Even more interesting was a converse (vis-a-vis this blog) discovery, that Tamoxifen which is traditionally used for breast cancer, may be useful as an off-label treatment for primary biliary cirrhosis (Reddy et al. Liver Int., 2004 Jun;24(3):194-7)!  So thank you Noreen for leading me to a treasure trove of discoveries!

What is Urso?

Ursodiol or Ursodeoxycholic (Actigall, URSO) is a naturally derived bile acid that decreases the amount of cholesterol produced by the liver and absorbed by the intestines. Interestingly, ursodiol is found in large quantities and the major therapeutic ingredient in bear bile, which is an established if controverial member of traditional Chinese medicine’s pharmacopoeia. Ursodiol helps break down cholesterol that has formed into stones in the gallbladder and is also hepatoprotective. Ursodiol also increases bile flow, which is why it is useful in cholestatic conditions such as biliary cirrhosis.  Since the 1980’s, Urso has been in widespread clinical use for biliary conditions. But what surprised me when researching the potential application of Urso for Noreen’s case is the anti-cancer properties of Urso.

Urso and Cancer

Earnest DL et al. from the U. of Arizona reported as early as 1994 that Urso is a potential chemopreventative agent in experimental colon cancer and highlighted a role of bile salts in modulating gastrointestinal cancer development, and it wasn’t long before Urso became a recognized chemopreventative agent against colon cancer in those with inflammatory bowel disease (See Itzkowitz SH, Gastroenterol Clin North Am. 2002 Dec;31(4):1133-44).  In 1997, the Korean team Park YH et al. reported that Urso induced apoptosis (suicide) of liver cancer cells in vitro (Arch Pharm Res. 1997 Feb;20(1):29-33) and the same team further demonstrated derivatives of Urso had efficacy against prostate and breast cancers in later studies. Im and Martinez more recently demonstrated that Urso induced apoptosis in colon cancer partly via modulation of EGFR/Raf-1/ERK signaling (Nutr Cancer. 2005;51(1):110-6.) A most recent review of Urso as an apoptotic is found in a review by Amaral JD et al. in J Lipid Res. 2009 May 5.

Granted, clinical data for Urso as a cancer treatment is not available and its main potential seems to be the use as chemopreventative in those at high risk for colon or liver cancers to reduce the risk, but attempts to synthesize Urso and other bile salt derivatives for cancer treatment is already on the way.

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Noscapine near perfect?

Solid science, potential efficacy, minimal toxicity and low cost – that would be a nearly perfect anti-cancer, wouldn’t it?

This is not an entirely new one.  Noscapine (also, see NCI drug dictionary) a naturally derived and existing ingredient of OTC cough medicines in some countries, it has more data backing its usefulness against cancer than its relative Naltrexone (a fellow off-label anti-cancer candidate which is opiate derived) and works like the chemo drug paclitaxel (Taxol) but without many of the nasty side-effects, all of which has been known for some time.

So, what is Noscapine?  It is a non-opiate alkaloid from plants of the poppy family that makes up 1-10% of opium’s alkaloid content, but without significant pain killing properties. This agent is primarily used for its antitussive (cough-suppressing) effects, and is approved for use as such in some countries, but not in the US.

Mechanism of Action

A review by Ye et al. from Emory, where much subsequent in vitro and in vivo research on its anti-cancer effects were done, presented as early as 1998 (Proc Natl Acad Sci, 17;95(4):1601-6.) demonstrated elegantly how Noscapine may inhibit cancer by interfering with microtubular function at the cellular level, thereby arresting cell growth and  inducing cellular suicide or apoptosis, much like taxanes and the vinca alkaloids do. Noscapine binds to tubulin and alters its conformation, resulting in a disruption of the dynamics of microtubule assembly (by increasing the time that microtubules spend idle in a paused state) unlike other tubulin inhibitors such as the taxanes and vinca alkaloids which affect microtubule polymerization. Perhaps more importantly, Noscapine was able to inhibit cancer at doses which produced little or no toxicity, including no adverse effects on the primary immune response (Ke Y et al. Cancer Immunol Immunother. 2000 Jul;49(4-5):217-25).  More recently, Newcomb et al. from New York also demonstrated potential anti-angiogenic activity of Noscapine as an alternate anti-cancer mechanism (Int J Oncol. 2006 May;28(5):1121-30)

In Vitro

Noscapine inhibits paclitaxel resistant ovarian cancer cells (Zhou, J et al. J Biol Chem. 2002 Oct 18;277(42):39777-85); C6 rat glioma when administered alone, (as well as augmented the cytotoxicity of radiation and chemotherapy upon C6 rat glioma cells when administered concomitantly – Surg Neurol. 2006 May;65(5):478-84), HL60 and K562 myelogenous leukemic cells Anticancer Drugs. 2007 Nov;18(10):1139-47),

In Vivo

Noscapine inhibits murine lymphoid tumors,  human breast and bladder in nude mice murine (Ye, 1998), prolonged survival in melanoma (Landen et al. Cancer Res. 2002 Jul 15;62(14):4109-14), crosses the blood brain barrier and inhibited implanted C6 glioma in the rat model (Landen, Clin Cancer Res. 2004 Aug 1;10(15):5187-201), and has potent anti-cancer activity in the non-small cell lung cancer model Cancer Chemother Pharmacol. 2008 Dec;63(1):117-26).

Generating the most buzz was the last year’s demonstration by Dr. Barken of San Diego of Noscapine’s ability to inhibit progression and metastates (60% and 65% respectively) inPC3 human prostate cancer-bearing immunodeficient mice Anticancer Res. 2008 Nov-Dec;28(6A):3701-4.)

Clinical (human) Studies

Unfortunately, although a phase I/II clinical trial of Noscapine (CB3304) for patients with refractory non-Hodgkin’s lymphoma and chronic lymphocytic leukemia at USC / Norris Cancer Center was planned in 2003, it was terminated early because of apparent funding issues.  However, interim results in 2005 on 12 patients recruited thus far suggested that one out of ten patients evaluable did have a partial response, and two other patients demonstrated stable disease.  The research team stated that they were encouraged by the results. Cougar Biotech Inc. currently has a phase I trial of noscapine in patients with multiple myeloma ongoing at the Center for Lymphoma and Myeloma/Weill Cornell Medical College and Columbia University Medical Center, and Dr. Barken of the Prostate Cancer Research and Educational Foundation (PC-REF) in San Diego, California, is planning on facilitating clinical trials with noscapine in prostate cancer.

My Take

Potentially useful against CLL leukemia/lymphoma/myeloma, prostate cancer, non-small cell lung cancer, glioma (administered alone or in combination with chemo and/or radiation to enhance cytotoxicity), hormone resistant breast cancer, or perhaps co-administered with taxanes.

Distinct advantages include i) oral bioavailability, ii) encouraging experimental data, iii) low toxicity, iv) low cost, and v) synergistic potential with other modalities and drugs.

The future lies with more affirmative clinical trials and the development of more potent derivatives such as 9-bromonoscapine (Mol Cancer Ther. 2006 Sep;5(9):2366-77) and to develop other analogs of Noscapine with higher tubulin binding activity  and/or affect tubulin polymerization differently, or able to arrest cell cycle progression at lower concentrations.

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Clarithromycin for lung cancer

February 26, 2009 1 comment

Advanced comments welcome … In the process of reasearch and writing up, thank you for your patience !

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Artesunate and Antimalarials for Cancer

February 26, 2009 2 comments

Advanced comments welcome … In the process of reasearch and writing up, thank you for your patience !

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Gamma-Delta Immunotherapy

February 23, 2009 4 comments

A Preamble

γδ T cells or “gammadelta” T cells are unique to primates and represent a minority white cell in our blood (0.5-5%); yet they play an essential role in sensing ‘danger’ by invading pathogens as they expand dramatically in many acute infections and may be a key fighter in cancer as well.  I want to discuss very exciting findings of how to harness these cells as an anticancer strategy but why does it belong in this blog?

Technically, gammadelta therapy is an immune therapy and is not “off-label” per se, because since these are a patient’s own cells, there is no issue of FDA approval or non-approval, and thus no issue of being on or off-label !   But, the key here are the drugs used to expand gammadelta T cells to use them to fight cancer are approved for other uses and these agents can be used off-label to direct the expansion of gammadelta T cells, hence the mention of this treatment here.

I am not easily excited, having been “in the business” if you will for decades and having seen so many mediocre agents and methods come and go in our “war against cancer” where true advance has been been disappointingly few.  But this time we may be on to something truly special.  The title of a recent review article by N Caccamo of Italy “Amiophosphonate-activated gammadelta T cells in immunotherapy of cancer: Doubt no more” ( Expert Opin Biol Ther 2008 Jul; 8:7, pp. 875-883) sums up the excitement.

Some Background

The background is not necesarily an easy one to understand if you do not have a science or medical background.  There are surprisingly few general introductory books on the topic, but the dated (1992) paperback “The Transformed Cell” by Steven Rosenberg is still a good primer for those who are interested but not necessarily want to earn college credit on the subject. And if you are not much interested at all in how this method works and all the immunology mumbo jumbo, but just want to know the practicalities of the treatment, you may as well skip to the last 2 sections to avoid a headful (and a headache!).

I have also put in BOLD some key concepts here in  order to highlight the key concepts for non-scientist or patients to help understand all this.

We as mammals have two innate immune defense systems:  an adaptive immune system unique to vertebrates in which lymphocytes participate with recognition of peptide antigens and which can be defined by memory of the target; and a more ancient innate immunity which is cell based (macrophages, monocytes, NK cells, NKT cells, dendritic cells) and which has no memory once demobilized.  The gammadelta cells can be thought of as unconventional T cells at the interface between and linking the two immune systems, and contribute to the elimiation of infections or cancers by direct and indirect killing as well as modulation and stimulation of other immune cells (eg macrophages and NK cells) and the secretion of cytokines, notably interferon gamma and TNF-alpha.

Gammadelta T cells were known since the time when I was graduating medical school, in the mid to late ’80s (See Lanier et al. The gamma T cell antigen receptor. J Clin Immunol 1987;7(6):429-40 and Pardoll et al., The unfolding story of T cell receptor gamma, FASEB J, 1987; 1(2):103-9.) and it became known  that gammadelta T cells can kill tumor cells.  However, over the years, these cells received much less attention than Natural Killer (NK) cells, NKT lymphocytes and the much more populous alphabeta T cells in regards to applications in cancer immunotherapy.

The use of killer cells against cancer has been a focus of research for nearly two decades. Since the original descriptions of in vitro lymphocyte-mediated cytotoxicity against cancer, there have been numerous quasi-sucessful attempts to exploit these for therapeutic use in the clinic.  I say “quasi-successful” because there are no mind blowing successes, regretfully.  Most modern research have focused on the role of either natural killer (NK) cells or cytotoxic CD8 + alphabeta T cells , and little attention has been paid to the role of gammadelta T cells due to a lack of understanding of how they work, as well as the practical problem of obtaining enough of them for bedside use.  Our clearer understanding of these cells and their role in infections, cancer and autoimmunity is only surfacing recently (The first world conference on gammadelta T cells only got under way in 2004).

Gammadelta cells share with alphabeta T cells certain functions such as cytokine production and potent cytotoxic (cell killing) activity but gammadelta cells recognize different sets of antigens, usually in a non-MHC-restricted fashion, and cancers are highly susceptible to gammadelta T-cell mediated lysis which led to the proposal that gammadelta T cells can be used for cancer immunotherapy (See Kabelitz D, Potential of human gammadelta T lymphocytes as immunotherapy for cancer, Int J Cancer 2004 Dec 10;112(5):727-32). Unlike conventional T lymphocytes which recognize peptide antigens,  this “alternative” T cell’s ability to recognize tumor cell ligands not seen by conventional alphabeta T cells is one property that makes them intriguing. The other unique property is the way they recognize antigens circumvents to ability to of cancer cells to eventually elide detection.

In Vitro Work

It has long been known that these cells can kill cancers.

Gammadelta T cells are able to kill myeloma (Kunzmann et al. Blood, 2000; 96(2): 384-392, also Clin Exp Immunol, 2006;144(3):528-33) and lymphoma cells (Fisch et al. Europ J Immunol 1997;27:3368-3379)

Human Vgamma9Vdelta2+ gammadelta-T cells found able innately to recognize and kill certain human prostate tumor cell lines (DU-145 and PC-3 but not LNCaP) (Liu et al. J Urol, 2005;173(5):1552-6).

Gammadelta-T cells are able to innately recognize and kill human breast cancer cells in a gammadelta-TCR-dependent manner (Guo BL et al. Breast Cancer Res Treat 2005; 93(2):169-75.).

Freshly prepared gammadelta T cells consisting mainly of Vdelta2 gammadelta T cells showed increased cytotoxicity against bisphosphonate-treated pancreatic carcinoma cells (J Immunother 2007; 30(4):370-7)

Perhaps most exciting is the finding of efficient killing of cancer stem cells by gammadelta T cells (Todaro M, et al. J Immunol. 2009 Jun 1;182(11):7287-96).

In summary, most epithelial tumours (including melanomas, pancreatic adenocarcinomas, squamous cell carcinomas of the head and neck, and lung carcinoma – See Scan J Immunol, 2007;66(2-3):320-8) were susceptible to allogeneic gammadelta T-cell lysis and in the case of an established ovarian carcinoma, to autologous gammadelta T-cell killing

Animal Studies

Early on. Hayday found that mice lacking gammadelta cells were highly vulnerable to skin cancer when exposed to carcinogens.

A ‘St Jude’s regimen” utilizing human gammadelta T-cells from leukapheresis and adoptive transfer of the cells with an anti-GD2 antibody and the cytokine Fc-IL7 demonstrated enhance survival in a mouse model of human disseminated neuroblastoma (Clin Cancer Res 2005;11(23):8486-8491.

In models of mice bearing localized and disseminated prostate cancer treated i.v. with gammadelta T cells developed measurably less disease and superior survival compared with untreated mice (Liu Z, J Immunol, 2008;180(9):6044-53).

Intravesical administration of gammadelta T cells with zoledronic acid demonstrated antitumor activity against bladder cancer cells in the orthotopic murine model and resulted in prolonged survival (Yuasa T et al. Cancer Immunol Immunother 2009;58(4):493-5020

Recently published study ( Jul 2010) out of the U. of Alabama demonstrated efficacy of adoptively transferred gammadelta-T cells in both syngeneic (4T1) and xenogeneic (2Lmp) models of breast cancer, and the treatment was otherwise well-tolerated by treated animals. (Beck BH et al. Breast Ca Res Treat. 2010 Jul;122(1):135-44)

Stimulating and Expanding Gammadelta T Cells is Key.

Just knowing gammadelta T cells can kill cancer cells is not enough.  We and cancer patients all have these cells, but how to harness them to fight cancer in us or our patients? The limitations up until late ’90s has been the difficulties associated with identifying, harvesting, and expanding the cells. Thus the  key is in growing or expanding these cells either in the laboratory and externally applying the cells to the patient ( so-called adpotive therapy) or to stimulate and expand the gammadelta cells in our bodies somehow.  Both have been looked into:

Gammadelta cells is known to be stimulated by a number of non-peptide phosphorylated antigens, including a number of mycobacterial and bacterial derived molecules as when one encounters when one catches one of these infections (eg TB, E.Coli), as reported since the early ’90s.  Reports of gammadelta stimulation and expansion by small phosphorylated metabolites, amino-bisphosphonates (risedronate>alendronat>pamidronate) and synthetic phosphoantigens (defined as small, phosphorus-containing antigenic molecules) followed, openning up the opportunity of clinically applying this as a practical cancer treatment (reviewed by Fourniee and Bonneville in Res Immunol, 1996;147(5):338-47).

Pioneering work by the Italian team Casetti et al. elegantly demonstrated that co-stimulation simply with interleukin 2 plus non-peptide antigens or amino -bisphosphonates induced up to 100-fold increases in the numbers of peripheral blood Vgamma9Vdelta2 T cells in animals and together with a German team led by Wilhelm M et al. (see below, this laid the ground work for subsequent clinical endeavours in this field (Casetti R et al. Drug-Induced Expansion and Differentiation of V{gamma}9V{delta}2 T Cells In Vivo: The Role of Exogenous IL-2, J Immunol 2005;175(3):1593-8).

Exciting Human Observations and Clinical Data

In the past few years, clinical data has been pouring in fast and furious suggesting practicability and efficacy of this unique therapy.

In 2005, Bennouna et al. presented a phase I trial of 18 BrHPP (Phosphostim) and low dose IL-2 treated patients with solid tumors in a poster session at ASCO (JCO, 2005; 2005 ASCO Annual Meeting Proc 23(16S), Pt II of II:2536).

By 2007, Godder KT et al. from the US reported intriguing 5 year follow-up results showing three-fold overall survival advantage in acute leukemics with increased gammadelta cells following partially mismatched allogeneic stem cell transplantation, and postulated a graft versus leukemia effect (Bone Marrow Transplant 2007;39(12):751-7).

One of the earlier trials using gammadelta therapy was carried out by a German team from Wuerzberg utilizing low-dose interleukin 2 (IL-2) in combination with pamidronate in patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). They observed significant in vivo activation/proliferation of gammadelta T cells in 5 out of 9 patients (55%) who had positive in vitro response to pamidronate / IL-2 stimulation and objective responses (PR) were achieved in 3 patients (33%) . And thus the team demonstrated for the first time that this therapy was feasible (Wilhelm M. et al, Gammadelta T cells for immune therapy of patients with lymphoid malignancies, Blood, 2003;102(1):200-6).

Recently, a Japanese team from Tokyo attempted adoptive immunotherapy using in vitro-activated autologous gammadelta T cells against advanced renal cell cancer had found that it was well tolerated and induced anti-tumor effects (kobayashi H. et al, Cancer Immunol Immunother. 2007 Apr;56(4):469-76) . A French team using gammadelta T cells expanded in vivo with BrHPP (IPH1101, Phosphostim) and interleukin 2 (IL-2) at administered by infusion to metastatic renal cell cancer patients resulted in stable disease in 6 patients out of 10 (Bennouna J. et al. Cancer Immunol Immunother 2008;57(11):1599-609).

Almost simultaneously, the Italian team led by Dieli F of Palermo initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility of using zoledronate in combination with low-dose interleukin 2 (IL-2) to stimulate gammadelta cells against the cancer and registered 3 partial remissions and five stable diseases out of nine patients (Dieli et al. Cancer Res.2007;67(15):7450-7) .

The same team above from Palermo also reported positive results in a small trial in May of 2010 of using zoledronic acid with low dose IL-2 in 10 “therapeutically terminal, advanced metastatic” breast cancer patients. Treatment was well tolerated and there was a statistically significant correlation of clinical outcome with peripheral Vgamma9Vdelta2 T cell numbers, with three patients who sustained robust peripheral Vgamma9Vdelta2 cell populations after treatment responding with declining cancer markers and partial remission or stable disease (Meraviglia S, et al. Clin Exp Immunol. 2010 May 10 Epub ahead of print), while a Japanese team almost simultaneously reported in Feb of 2010 thr complete remission of a patient with lung metastasis from renal cell carcinoma after six cycles of autologous in vitro-activated gammadelta T-cells followed by low-dose interleukin-2 and zoledronic acid intravenous infusion. Complete remission was achieved which has been maintained for 2 years without any additional treatment (Kobayashi H, et al. Anticancer Res 2010 Feb;30(2):575-9)

At the moment, there has been trials including a study of the use of gammadetla therapy in recurrent non-small cell lung cancer at the U. of Tokyo in Japan and an active phase I trial “Immunotherapy of Hepatocellular Carcinoma With Gamma Delta T Cells” which involves the direct intrahepatic injection of gammadelta cells going on in Rennes, France under the direction of Dr. Jean-Luc Raoul.  Researcher Lamb LS Jr. and team at the U. of Alabama have also been exploring explores graft engineering techniques in the development for the therapeutic use of gammadelta T cells against glioblastoma multiforme (Immunol Res. 2009;45(1):85-95)

My Take

Although we have known about gammadelta cells, but the ability to use fairly straightforward medicines such as the amino-bisphosphonates and interleukin-2 off-label to dramatically expand these cells in a patient without serious side-effects opens the way to a practical immunotherapy.  The fact that there is laboratory data showing efficacy against leukemia/myeloma and also human experience which is positive for some solid tumor (prostate, breast, lung and kidney) cancer types gives hope that this treatment can be broadly deployed against an array of cancers, both hematologic and solid tumors.  Research finding that the therapy can efficiently kill cancer stem cells is also exciting.  Most importantly, that this therapy calls for a protocol that is much more simple (30 minute treatment every month) than the parenteral Vitamin C protocol with much more science behind it than IPT (Insulin Potentiation Therapy) and other “alternative” cancer regimens makes this a very attractive options for patients seeking an alternative to conventional chemotherapy or radiotherapy.  Although NK cells are much more popularly known but there is no practical way to expand NK cells in the patient but this gammadelta therapy is eminently praticable.  My colleague Dr. Thomas Nesselhut at the Institut of Tumortherapie in Duderstadt, Germany is starting to apply this as a part of the Dendritic Cell therapy protocol that we have been collaborating on for the past 5 years and it appears quite promising.  We are currently gearing up to offer this as a viable alternative therapy while working out some of the legal and logistics hurdles to deployment.  All very exciting indeed.  Your comments welcome !

Future Directions

-> Clinical trials covering other cancers beyond prostate, kidney, myeloma. and NHL.

-> Development of more potent gammadelta stimulants or expansion protocols.

-> Exploring naturally-derived gammadelta agonists for dietary preventative therapeutic regimens.

-> Exploring the preventative possibilities of gammadelta therapy

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