On CSC and therapeutic sensitivity studies

If cancer stem cells are resistant to current therapies, what’s next? by Paola Marcato‌, Cheryl A Dean‌, Carman A Giacomantonio‌ and Patrick WK Lee‌, Future Oncol 2009(Aug); 5(6): 747-50. [Twitter entry][FriendFeed entry][PubMed Citation]. Excerpts from the final portion of this Editorial:

Thus far, oncolytic viruses as a class of novel cancer therapeutics appear to kill CSCs with the same efficiency as non-CSCs [references]. Therefore, the characteristics that make CSCs resistant to current therapies do not limit the ability of the viral-based therapies to infect and kill these cells. Of further interest is the possibility of engineering oncolytic viruses to specifically kill tumor cells that express CSC markers.

We conclude that with increasing evidence that CSCs are potent initiators of cancer and have an intrinsic resistance to current therapies, scientists and clinicians will need to rethink traditional end points, such as tumor regression, as the major indicator of the efficacy of anticancer therapies, new and old.

Translation of knowledge about CSC into clinical use

Radiation Therapy Oncology Group Translational Research Program Stem Cell Symposium: Incorporating Stem Cell Hypotheses into Clinical Trials. Authors: Wendy A Woodward, Robert G Bristow, Michael F Clarke, Robert P Coppes, Massimo Cristofanilli, Dan G Duda, John R Fike, Dolores Hambardzumyan, Richard P Hill, Craig T Jordan, Luka Milas, Frank Pajonk, Walter J Curran, Adam P Dicker, Yuhchyau Chen. Int J Radiat Oncol Biol Phys 2009(Aug 1); 74(5): 1580-91 [Epub 2009(Jun 17)]. PubMed Abstract:

At a meeting of the Translation Research Program of the Radiation Therapy Oncology Group held in early 2008, attendees focused on updating the current state of knowledge in cancer stem cell research and discussing ways in which this knowledge can be translated into clinical use across all disease sites. This report summarizes the major topics discussed and the future directions that research should take. Major conclusions of the symposium were that the flow cytometry of multiple markers in fresh tissue would remain the standard technique of evaluating cancer-initiating cells and that surrogates need to be developed for both experimental and clinical use.

More on immune based therapies for the treatment of cancers

ImmunoCellular Therapeutics Retains Services of Torrey Pines Institute for Molecular Studies and Renowned Immunologist to Evaluate Lead Product Candidate, Business Wire, July 14, 2009. Excerpts:

ImmunoCellular Therapeutics, Ltd. (OTCBB: IMUC), a clinical-stage biotechnology company that is developing immune based therapies for the treatment of brain and other cancers, announced today that it has retained the services of the Torrey Pines Institute for Molecular Studies in San Diego, CA, to evaluate the immunogenicity of peptides to target cancer stem cells (CSC’s) relating to the Company’s lead product candidate ICT-121. The evaluation will be conducted by Dr. Clemencia Pinilla, a specialist in immune response mechanisms and their role in the prevention and cause of human disease with over 100 publications and multiple patents to her credit.

.....

ICT-121 is IMUC’s cancer stem cell (CSC) vaccine product candidate that consists of a peptide to stimulate a cytotoxic T-lymphocyte (CTL) response to CD133, which is generally overexpressed on the CSCs.

Relevant links: Profile of Clemencia Pinilla, of the Torrey Pines Institute for Molecular Studies in San Diego, California; and, Opinion: A Stem of Hope for Cancer Treatments by Manish Singh (President and CEO of IMUC), Genetic Engineering & Biotechnology News, June 12, 2009. [Previous blog post: Bright future for CSC therapies?, June 14, 2009].

Note that it is important that CSC-targeted vaccination "should not lead to immune reaction to normal cells that may express common antigens". For a recent publication from which this quotation is taken, see: Antigen-Specific T Cell Response from Dendritic Cell Vaccination Using Cancer Stem-like Cell-Associated Antigens by Qijin Xu and 8 co-authors, including John S Yu, Stem Cells 2009(Apr 23) [Epub ahead of print][PubMed Citation]. (John S Yu is Chief Scientific Officer and Chairman of the Board of IMUC, see: Our Team - IMUC).

For some background about immune based therapies for the treatment of cancer, see: Cancer Vaccines by Preeti Gokal Kochar, ProQuest Discovery Guide, January 2006.

See also: Connotea bookmarks matching tag CD133.

Article in the San Francisco News

Stem-cell stalemate: The push for cures may produce only disappointment - or worse, Peter Jamison, San Francisco News, April 14, 2009. Excerpt from page 5:

And CIRM's 2009 funding priorities speak volumes about the direction of its decision-making. In its first two years of operating — legal challenges kept CIRM from starting its operations until 2007, setting back its sunset date to 2017 — the agency has distributed more than $600 million in grants for basic science and facilities. By contrast, the next round of grants will devote more than $200 million to disease teams; the goal for these teams is to prepare therapies for FDA clinical trials within four years. As little as $20 million will go to basic research.

Found via: The California Stem Cell Story: Safety, Waste and Promises, David Jensen, California Stem Cell Report, April 15, 2009.

Guidelines for the Clinical Translation of SC

Guidelines for the Clinical Translation of Stem Cells, International Society for Stem Cell Research (ISSCR), December 3, 2008. Links are provided to the Guidelines [PDF], to Apppendix 1 (a Patient Handbook on Stem Cell Therapies) [PDF], to Appendix 2 (Additional Resources), to a Cell Stem Cell article summarizing the essential elements of the document [PubMed Citation] and to a joint ISSCR and Cell Stem Cell Press Release about the Guidelines.

For an article, in the same issue of Cell Stem Cell, that provides evidence that such Guidelines are needed, see: Stem Cell Clinics Online: The Direct-to-Consumer Portrayal of Stem Cell Medicine by Darren Lau and 5 co-authors, including Timothy Caulfield, Cell Stem Cell 2008(Dec 4); 3(6): 591-4. PubMed Abstract:

Despite the immature state of stem cell medicine, patients are seeking and accessing putative stem cell therapies in an "early market" in which direct-to-consumer advertising via the internet likely plays an important role. We analyzed stem cell clinic websites and appraised the relevant published clinical evidence of stem cell therapies to address three questions about the direct-to-consumer portrayal of stem cell medicine in this early market: What sorts of therapies are being offered? How are they portrayed? Is there clinical evidence to support the use of these therapies? We found that the portrayal of stem cell medicine on provider websites is optimistic and unsubstantiated by peer-reviewed literature.

See also: Laws needed to protect patients from stem cell clinics' exaggerated claims: study by Sheryl Ubelacker, Canadian Press, December 3, 2008. The first sentence:

Canadians should be "very skeptical" of foreign clinics that use websites to promote stem cell therapies for a wide range of medical conditions, warn researchers, saying there is a dearth of scientific evidence to back up their claims.

Comments: The Guidelines contain no explicit mention of cancer SC. However, if one accepts the prediction that "diagnostic methods based on the detection of CSC’s will have the potential to address key limitations of current methods" [excerpt from Business Wire, April 26, 2007], then some attention needs to be paid to the known limitations of diagnostic methods. Two examples of relevant references:

1) Grading quality of evidence and strength of recommendations for diagnostic tests and strategies by Holger J Schünemann and 10 co-authors, including Gordon H Guyatt, BMJ 2008(May 17); 336(7653): 1106-10 [PubMed Citation]. Excerpt from the publicly-accessible Extract:

Inferring from data on accuracy that a diagnostic test or strategy improves patient-important outcomes will require the availability of effective treatment, reduction of test related adverse effects or anxiety, or improvement of patients’ wellbeing from prognostic information.

Excerpt from the full text:

Although recommendations on diagnostic testing share the fundamental logic of recommendations on treatment, they present unique challenges.

2) See also: Evaluation of clinical innovation: a gray zone in the ethics of modern clinical practice? by Johane Patenaude and 4 co-authors, J Gen Intern Med 2008(Jan); 23(Suppl 1): 27-31 [PubMed Citation]. Excerpt for the Conclusions section of the (publicly accessible) full text:

Innovation is a neglected area for ethics assessment. Further studies on a larger scale are necessary to review the concepts of experimental, innovative, and commonly accepted care.

Perhaps a subsequent version of the ISSCR Guidelines should include a section on diagnostic tests involving CSC?