Historic Boston Globe editorial on FDA, stem cells & patients argues safety first

For the first time I have ever seen in at least half a dozen years, a major newspaper in the form of The Boston Globe has published an editorial on FDA regulation of stem cells.

Boston Globe

The editorial, entitled “It should be safety-first on stem cell therapies”, argues that while we should take patient concerns into consideration, it must be safety first on experimental stem cell therapies.  I commend them for this editorial and their common sense approach to this hot topic.Stem Cell Medicine

It’s great that the Globe places this opinion in the context of the upcoming FDA public hearing on regulations related to stem cells. The Globe’s opinion carries great weight and appears supportive of the FDA.

The Globe piece closes this way:

“The FDA has scheduled a public hearing on April 13 to solicit comments on draft guidelines it released last fall to clarify the use of stem cells. Under those guidelines, most cells would have to meet the same regulatory standards that apply to drugs. That concerns some patient advocacy groups, including the Alliance for the Advancement of Cellular Therapies and Patients for Stem Cells. They worry about approval procedures that could drag on for years, and they say denying patients control over the use of their own cells amounts to a civil-liberties violation. Those concerns deserve consideration, but patients also need to trust that any treatment they seek from a licensed physician or medical center has passed muster with the FDA. When stem cells are used as medicine, they should be regulated as medicine.”


26 thoughts on “Historic Boston Globe editorial on FDA, stem cells & patients argues safety first”

  1. @Bill – your question, “If a doctor aspirates normal bone marrow from a healthy, cancer-free patient…and then injects it into the patient’s knee…do you think that “might cause cancer”…?

    YES – because “might” means there is a certain risk, however small, and there’s always a risk when proliferating cells are injected, that’s nothing new.

    The real question is how great the risk is and does the benefit outweigh it? For bone marrow transplant, secondary cancer risk is 1-2%, but you take the risk to save your life. For joint therapy far fewer cells are used and risk is likely to be much lower – but still not zero.

    This is described in Paul’s excellent discussion here, http://www.ipscell.com/2012/04/the-real-but-oft-ignored-dangers-of-adult-stem-cell-treatments/

  2. Jeff – There are reports of cord-blood being more potent than adipose but I don’t know of any quantitative studies on the relative immune suppressive (or angiogenic) activities of adult stem cells. A full characterization in an appropriate system would be a useful document for comparative cell biology and clinical efficacy.

  3. @Independent, thanks for the infos. Fascinating how the immune system is so important for cancer control. I’ve also seen this with potent immune suppressive drugs in autoimmune therapy. Do you know of any literature on the relative potency of different types of stem cells to block immune activity compared to small molecules and therapeutic antibodies?

    @Bill – I think you’re barking up the wrong tree as a single case (n=1) is not proof either way. Clinical trials aren’t done to determine causality (mechanism), but to get a handle on efficacy and safety. The data for bone marrow transplantation show very clearly that cancers are induced so there is a real risk.

  4. @Jeff Please keep in mind that @Independent has still not cited a single case of autologous bone marrow aspirate concentrate causing cancer. Lots of “yea buts” and “what ifs” though.

  5. @Jeff – good question. Firstly one key observation – immune suppression reduces the body’s ability to identify and destroy cancer cells and carcinogenic viruses.

    Bone marrow ablation (myeloablation) with radio- and/or chemotherapy is used to kill existing bone marrow cells, which contain cancer cells in lymphoma, before new donor stem cells are injected. But the side effect is knocking out of the immune system for a while, so there’s an increase in unregulated growth of cancer cells and viral infections, such as Epstein-Barr Virus.

    But secondary cancers also occur without myeloablative treatment, so where do they come from? Studies demonstrate, i) that more secondary tumors are seen after treatments that cause donor stem cells to be “damaged”, such as pretreatment to increase numbers or expansion in culture or storage (cryopreservation), ii) the immune suppressive and angiogenic activity of some stem cells results in a growth advantage for existing cancer cells (see above), iii) the presence of cancer stem cells within the donor population. Any of these could result in tumor formation by donor stem cells. There is also the potential for unregulated growth of stem cells and it is well known that bone marrow aspirate concentrate contains multiple types of stem cells, including multipotent precursor cells.

    I have not weighted the risks as this is the job of clinical trials, but for any therapy the risk/benefit ratio must be determined, for example with the low doses used for joint injuries there may be lower, but not zero, risk.

  6. @Independent – If a doctor aspirates normal bone marrow from a healthy, cancer-free patient, spins it in a centrifuge and then injects it into the patient’s knee (synovial fluid), do you think that “might cause cancer” in his or her knee? Really?

  7. @Independent – By the way, specifically which of the 19 examples you’ve provided conclude that autologous stem cells CAUSED cancer in a previously cancer-free patient?

  8. @Independent – Once again, please cite just one documented case of autologous bone marrow aspirate concentrate CAUSING cancer in a patient or clinical trial subject. Or just admit that you cannot.

  9. @The Independent, I agree about the risk assessment and there is a certain risk for all types of stem cells to cause cancer by several means but isn’t this overestimated in bone-marrow transplants because new cancers are likely to be caused by the radiotherapy and chemotherapy that these patients also get?

  10. Bill, I’ve spent some time gathering the proof and references for you – if you don’t understand their import from a scientific and clinical testing perspective, I cannot help you further.

    My aim was solely to answer your original question regarding “…n=0 narratives like “autologous stem cells might cause cancer””

    Now you have n=3000 for which autologous stem cells might have caused cancer. So, QED on your question and good luck to you.

  11. @independent Since you brought it up first, please keep it respectful. You’re 0 for 19 now and I’m still waiting. Once again, please cite just one documented case of autologous bone marrow aspirate concentrate CAUSING cancer in a patient or clinical trial subject.

  12. @Bill – ever heard of Google? 😉 Oh well, just to save you the effort – about 50,000 bone-marrow stem cell (BMSC) transplants are performed each year and 57% of these are autologous. The incidence of secondary cancers in tumor patients or primary cancers in non-tumor patients receiving BMSC is 1-2%. Which means at least 150 cases of cancer in patients receiving autologous bone marrow aspirate every year. That’s n=3000 in the last 20 years.

    1. Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol. 1994 12:2535-42.
    2. Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy. Blood. 1994, 83:3780-6.
    3. Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin’s disease. Blood 1998, 92:1933-40.
    4. Second malignancy following high-dose therapy and autologous stem cell transplantation: incidence and risk factor analysis. Bone Marrow Transplant. 2003, 32:915-23.
    5. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003, 21:1352-8.
    6. Secondary solid cancer screening following hematopoietic cell transplantation. Bone Marrow Transplant. 2015, 50:1013-23.
    7. Solid cancers after bone marrow transplantation. N Engl J Med. 1997, 336:897-904.
    8. Solid cancers after bone marrow transplantation. J Clin Oncol. 2001, 19:464-71.
    9. Increased incidence of solid malignant tumors after bone marrow transplantation for severe aplastic anemia. Blood. 1991, 78:277-9.
    10. Poor clinical outcome of patients developing malignant solid tumors after bone marrow transplantation for severe aplastic anemia. Leuk Lymphoma. 1992, 7:419-23.
    11. Malignant neoplasms following bone marrow transplantation. Blood. 1996, 87:3633-9.

    So once again, bone-marrow aspirate concentrate, which contains BMSC, has a definite potential (1-2% for n=3000) of promoting cancer growth under certain circumstances.

    So where’s your data on the 60% success rate and the explanation why autologous bone marrow aspirate is not the same as BMSC? Score is 3000 to 0 and counting.

  13. @Independent Again, let me know when you can show me a single documented case of bone marrow aspirate concentrate causing cancer in a patient or clinical trial subject. So far, you are 0 for 8.

  14. No Bill – a comprehensive “yes”. But you need to understand the terminology and the scientific principles behind credible demonstration of proof and I don’t know where you are on this.

    A trivial aspect is your use of “aspirate” as if this were something special – it isn’t and virtually all human bone-marrow transplants start with a human bone-marrow aspirate. Hence, “bone marrow derived mesenchymal stem cells” (BMSC) are the same as “bone-marrow aspirate concentrates” and other names. Likewise, reports on cancer growth caused by BMSC also refer to the bone marrow aspirate. Here’s a small selection of some 350 references from a PhD in our lab on the role of stem cells factors in the growth of cancer cells:

    1. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors. Zhang et al. Stem Cell Res Ther. 2013 4:70.
    2. Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells. Bergfeld et al. Mol Cancer Ther. 2014, 13:962-75.
    3. Bone marrow-derived cells and tumor growth: contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells. Roorda et al. Crit Rev Oncol Hematol. 2009, 69:187-98.
    4. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Quante M et al. Cancer Cell. 2011 19:257-72.
    5. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Karnoub et al. Nature 2007, 449:557-63.
    6. Mesenchymal stem cells contribute to tumor cell proliferation by direct cell-cell contact interactions. Roorda et al. Cancer Invest. 2010 28:526-34.
    7. Mesenchymal stem cells enhance growth and metastasis of colon cancer.
    Shinagawa et al. Int J Cancer. 2010 127:2323-33.
    8. Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer. Liu et al. J Biol Chem. 2011, 286:25007-15.

    If you still believe “bone-marrow aspirate concentrate” is not covered in the above reports, you will have to provide evidence to show that this definition refers to a different type of stem cell. Good luck with that.

    So once again, bone-marrow aspirate concentrate, which contains BMSC, has a definite potential to promote cancer growth under certain circumstances. No “bug-a-boo”, just fact.

  15. A long winded, “no”. Let me know whenever you find a patient or subject treated with autologous bone marrow aspirate concentrate gets cancer from it. Thanks.

  16. @Bill – I don’t restrict myself in the discussion to adult stem cells isolated in one specific method. Bone marrow aspirate concentrate contains bone marrow stem cells (BMSC) so these are the subject of the safety issue being discussed.

    That is unless you are claiming that the aspirate concentrate form of BMSC in some way makes them much safer than BMSC isolated by other means? Or for that matter, makes them safer than other multipotent adult stem cells, such as cord-blood and adipose-derived stem cells. Is that what you are claiming?

    I take the adverse effect reports for BMSC to be applicable to BMSC isolated in any fashion and hence bone marrow aspirate concentrate is as likely to promote cancer growth as any other BMSC.

    I doubt if there are specific reports of tumor induction by BMSC derived through each procedure, administered by each possible route for each possible use. But to indicate that these cells are safe due to lack of such a report is like saying smoking tobacco in a specific cafe on a Tuesday has never been shown to cause cancer and hence tobacco is safe. Obviously not true.

    So I guess to be more accurate one could say that – bone marrow aspirate concentrate has a finite change of causing cancer growth as documented by the use of BMSC over the last 50 years. Is that better than “might cause cancer”?

  17. @Independent You said, “there are many documented cases of stem cells promoting cancer growth” Since this discussion is specifically about bone marrow aspirate concentrate, I said, “Please cite one documented case of autologous bone marrow aspirate [concentrate] causing cancer.”

    So, I respectfully request that you please cite just one documented case of autologous bone marrow aspirate concentrate causing cancer in a patient or clinical trial subject.

    Otherwise, I think it would be more appropriate to state, “There are no documented cases of bone marrow aspirate concentrate causing cancer in patients or clinical trial subjects.” instead of scaring people with the “it might cause cancer” bug-a-boo.

  18. @Bill – not sure what case you’re referring to? As I said, there are sufficient reports to demonstrate that under certain circumstances stem cells can support cancer growth but obviously, stem cell therapy has been around for over 50 years and is very successful for some conditions. It depends on the risk/benefit ratio.

    RIchie’s post cited the injection of bone marrow aspirate into the eye, and other clinical trials are ongoing for use in joints, in the heart, or given intravenously. The consequences of different routes and target tissues can be huge.

    If clinical trials show clear benefit over risk, there may be applications that health agencies will accept (and fund). So far I haven’t seen such data but the night is still young.

    Btw, I am not answering for anyone, but trying to provide information to you and any other readers. You can take it or leave it, but please be respectful.

  19. @Independent please cite one documented case of autologous bone marrow aspirate causing cancer. Good luck!

    Also, it would be nice if @admin could answer for himself instead of having “Independent” do it for him.

  20. @Brian – it is usual to publish preliminary reports for experimental clinical therapies and Dr. Weiss is no different – his publications for trial NCT01920867 are listed on clinicaltrials.gov.

    Weiss JN, et al. Neural Regen Res. 2015 10:982. SCOTS for retinal and optic nerve diseases: a preliminary report – and – Weiss JN, et al. Neural Regen Res. 2015 10:1507. SCOTS for retinal and optic nerve diseases: a case report.

    In each report a single case study (n=1) is described without comparison to controls or other cohorts, So n=1 and although interesting, a success rate cannot be determined.

    According to you the success rate is 60% with 275 patients – but in the current trial he is trying multiple routes in different pathologies caused by damage to different types of cells. It is impossible to have a 60% cure rate with this type of trial design. The 60% is only a statement made by Dr. Weiss’ and is not backed up by independent data showing “significant improvement” over current therapy or placebo,

    “you should even be less of a fan of “n=0” narratives like ‘autologous stem cells might cause cancer'”
    Unfortunately, cancer growth is a side-effect of most immune suppressive therapies and there are many documented cases of stem cells promoting cancer growth. Stem cells are well known for their immune suppressive effects and this means a loss of immune surveillance of newly arising cancer cells, resulting in their unchecked growth. There is no reason to believe that autologous cells will be any different. This doesn’t even touch on the potential of multipotent stem cells to differentiate into ectopic or teratogenic tissue.

  21. @admin And lastly, since you are not a fan of “n=1” stories, you should even be less of a fan of “n=0” narratives like “autologous stem cells might cause cancer”.

  22. @admin – Try to keep your bias in check.

    Why would anyone expect them to publish data before August 2017, at the earliest? See below from clinicaltrials.gov

    The record also states that the primary purpose of this study is “Treatment”.

    Estimated Enrollment: 300
    Study Start Date: August 2013
    Estimated Study Completion Date: August 2017
    Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

  23. Dr. Weiss has operated on around 275 patients for this surgical procedure, doing about 16 to 18 surgeries a month. The surgery takes about 2.5 hours from start to finish, and it takes about a month for your eyes to heal.

    Dr. Weiss estimates 60 percent of his patients gain vision.

  24. Thanks for the link Richie – sounds like the usual “n=1” story, which you know is scientifically meaningless, but this is a clinical trial with n=300, so what happened to the other 299 patients? Is the success rate only 1/300?

    Also I don’t understand why that patient paid $20,000 for the treatment if this is a clinical trial with volunteers. If 300 patients paid a total of $6 million and only one patient was helped, that really is an amazing story – amazing for the clinic’s bank account.

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