Thu, 12 Jan 2012

Summary of Memorial Sloan Kettering Advisory Board Meeting

Larry Norton, MD
Depury Physician-in-Chief, for Breast Cancer Programs
Medical Director, Evelyn H. Lauder Breasr Cenrer
Norna S. Sarofim Chair of Clinical Oncology

Edward R. Flynn, Ph.D., Chief Scientist
Senior Scientific, LLC, a Manhattan Scientifics unit
800 Bradbury SE
Albuquerque, NM 87106

January 10, 2012

Dear Dr. Edward Flynn:

It is with great pleasure that I write this synopsis of the advisory board meeting that I had the honor to chair on October 31st, 2011. I thank you and your colleagues for the opportunity to gather highly qualified experts on cancer management and medical imaging and to hear an erudite presentation of the history and state of development of your technology. We had the opportunity to ask probing questions and were gratified by the quality and openness of the answers. Moreover, I was impressed with the creativity evident in the room. This was both on the parts of you and your scientific team and the parts of the advisors who synthesized the presentations and found a straightforward initial clinical application (described below). Since the transcript of the meeting details these discussions well, I would like to focus my remarks on the overall conclusions and general impression, which were shared and expressed by the entire advisory team.

The most obvious reaction was one of satisfaction with the extraordinary innovation and level of sophistication of the technology itself. Both the physics and chemistry (nanoparticle size) are at the highest level, blessed by simplicity of concept that is being developed with superb skill and scientific judgment. In addition, much has been accomplished experimentally. This includes the physics and chemistry but also biology, in that cells and live tissues have been examined and have been seen to confirm theoretical predictions. Even advisors who were initially skeptical (as befits quality scientists) were convinced of these points. The high specificity of antibodies coupled with the unsurpassed sensitivity of your detection methods raises this technology far over all known competitive approaches (which were detailed in our discussions).

Linearity in detection thresholds offers particular promise for the identification of cancer cells in small numbers, e.g. in lymph nodes containing tiny foci of disease or even dispersed single cells. The precise localization of lesions presents many possible merits. Hence, one general conclusion was that you possess highly valuable technology that can bear intense scrutiny and thereby earn the confidence of well-informed experts in medical imaging. In addition, the relatively low cost of the machinery that would be needed for clinical use compares so favorable with MRI and PET/CT that this would be another considerable advantage.

The second reaction, equally evident, was that the clinical applications could be myriad. These include (but are not limited to) early detection ofvarious cancers, mapping sites of malignant involvement, guiding invasive diagnostic or therapeutic (needle) interventions, monitoring of disease in response to therapy, monitoring immune response, identification in vivo of therapeutic chemical targets, measurement ex vivo of key molecules (such as HER2/neu) for prognostication and planning of therapy, and even- potentially-the detection of blood-borne circulating cancer cells. (Therapeutic applications, such as the destruction via applied magnetic energy of cancer cells taking up the reagents, were not discussed in detail.) Regarding applications, two barriers were identified that will need to be overcome as the research moves closer to or into applications to humans. The first is the choice of antibodies since not all common cancers are characterized by a ubiquity of cell-surface markers. Even in those cases when a marker is present, populations of cancer cells in any given patient are often heterogeneous in its expression. The second is that the reticuloendothelial system, particularly the liver, takes up the technology's reagents so as to possible obscure visualization in the abdomen. Metallic implantable devices present another potentially confounder. A third point-that safety in humans would have to be proven prior to clinical use-was raised and quickly discarded in that experience has already shown that both components of the reagents, antibodies with linkers and iron nanoparticles, are very unlikely to be deleterious or even poorly tolerated. Moreover, and perhaps most critical, the imaging methods use such low levels of magnetic forces as to be completely harmless to patients and technicians. This would be a welcome relief to cunent concerns about ionizing radiation safety with other modalities.

Regarding choice of disease to study and antibodies to use, there was a comprehensive discussion of epithelial neoplasms, which came rather quickly to a focus on cancers of the breast, ovary, endometrium, and prostate. Of these, HER2-positive primary breast cancer emerged as the dominant clinical issue for several clear reasons. This is a common disease. It presents in an organ that is not obscured by other tissues and is close to the surface of the body. The target protein- HER2- is found in a high percentage of the cells when it is present and the density of the protein per cell is extremely high in almost all cases. Several clinically-tested and well-tolerated antibodies are available for study and use, minimizing intellectual property concerns. The detection of multifocality in the breast could be of great clinical value, so a demonstration project could readily lead to a direct medical use. Additionally, the detection of involved axillary lymph nodes prior to or even in lieu of surgical biopsy could have significant worth, and would exploit the remarkable sensitivity of the technology. Prostate cancer-via PSMA-was al so considered and was relegated to a close second position in terms of ease of study and potential clinical utility. Ovarian carcinoma presented several problems that would need further work-lack of a common, high-density marker, lack of the demonstration so far of the utility of very early detection-so this would not, in the opinion of the advisors, to be the proper disease for first-in-humans trials. Of course, as the technology develops and the clinical utility is demonstrated, extension to mixtures of antibodies and to other conditions-such as lymph node mapping in gynecological neoplasms-could be considered.

Regarding the issues of confounding factors, the advising imaging experts felt that these could be overcome by the use of clearance rates in the liver vs. tumor and relaxation rates in metal vs. tissue. They did not feel that these were trivial issues, but neither were they insurmountable. However, because further research would be required to address them, an early focus on primary breast cancer- which would not present with these confounders-would be most prudent.

At the advisory board meeting there was considerable discussion regarding the topic of whether your technology was ready for human trials now or instead if further in vivo animal testing was required. Of course, standard large-animal toxicity evaluation and pharmacology development using animals would be needed prior to clinical trials, but the question was whether or not specificity/sensitivity needed to be addressed as well. For example, would the technique image a HER2-overexpressing tumor on one flank of a mouse while not imaging a contra lateral HER2-normal cancer (or a different type or the same type with HER2 knocked down by RNA interference) on the other flank? The advisors felt that while such experiments would be interesting and should at some point be conducted, that they were not necessary prior to first-in-human trials should safety be confirmed by standard methods.

Hence, the general impression of the advisors was positive and rather optimistic. Clearly, much needs to be accomplished, but the science is superb, the goals are clear and likely obtainable, and the results would almost certainly be clinically important given successful proof-of-concept in initial human studies. Indeed, there was a uniform enthusiasm among the participants from my institution in conducting an imaging trial in primary HER2-positive breast cancer (with HER2-negative controls) should a suitable apparatus for conducting such a trial be made available. Studies in prostate, ovarian, and other cancers could proceed following this initial evaluation. Therapeutic applications should be tabled at present pending the successful completion of diagnostic studies. Research in ex vivo uses, say in molecular diagnostics of biopsied tissues, should also be conduced since these are potentially useful, relatively inexpensive, and easier to perform from a regulatory viewpoint than human in vivo trials.

Again, I thank you for the opportunity to lead this advisory activity and stand ready as needs arise to answer any questions regarding our discussions.



Larry Norton, M.D.
Professor of Medicine
Weill Medical College of Cornell University

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