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NEW ENGLAND INSTITUTE FOR MEDICAL RESEARCH 4 4 Posr oFFRX BOX 3as RMGBFfBr.D, CoMNF.crtCerr may 18, 1964 Mr. J. Edgar Bennett Vice President and Assistant to President P. Lorillard Co. 200 9. 42 Street New York, New York Dear Mr. Bennett : Mr. H. H. Ramm, Vice President and General Counsel of the R. J. Reynolds Tobacco Company, recently informed us that he had discussed the possibility with attorneys of other leading cigarette companies that they might be interested in extending support to this Institute, as Reynolds does., Mr. Rammidid not name the person in your company whom he had discussed us with, but he suggested specifically that we contact you at your company. Mr. Ramm's interest in this Institute's findings arises from his knowledge of our basic medical research, including certain cancer studies, which the R.. J'. Reynolds Tobacco Company has supported annually since 1960 -- entirely outside of its support of the Tobacco Industry Research Council or the stud'yr of,smoking and disease which six cigarette companies are financing through the American Medical Association. Both of these organizations are concerned, at least ultimately, with a specific.relation between smoking and cancer, if one exists. We are not. Preventing or Cizrin Cancer Irrespective of Its Cause. Our research has the~objiectlve of preventing,and/or curing,cancer irrespective of what the carcinogenic ent may be. Our studies involve searching for a substa.nce which will stimulate the body to resist the onset of a!cancer, irrespective of its cause, and/or to effectuate its regressionior cure after such a cancer has started.Our first maj,or publication onithe effect of such a substance in malignan- cies will be given as a keynote presentation later this month in Japan at the Fourth International Symposium of the International Society for Research on the Reticuloendothelial System. Maed of Teusfeea: Lieut. Gen. Leslie R. Groves Colonel George C. Hras Dr: Joha H. HeII&' Dr. Marjorie Knauth George m. lOicCorkle Bdwxrd' L. Schnlz Robert T. Z'ate,, Jn. $dwdiilt Advlioryf deard: Dr. Walter L. Brown Dir.,Q:l:arles A: Doan Dr. William Von E. Doering Dr. Cluk Good'man Dr. Albert S. Gordon Dr. Robcrt' J., JeHries Dr. Gaald W: Jbhnaoa Dr. Joseph Kaplan Dr, Leo Pospisil', Adbherryr Couedt: Charlles D. Agnew Hon; Prescott Bush George C. H.as, Jr. A. S: Ho!pe, Jr. Wiioe-Ad'm. , George F.Aittpep. Jr. Thomas R. Jones Prof, , Harold D., Lasswell Francis D: Martin Robert P. Mountain liI'oo. Riit6and M, Nison Null A: Peaeley Harvey Picl<er, John L Senior, Jr. James' L. Turrentine Raymond j:,Wwn Atdm Yinkey, Jr.

Mr. J. Edgar Bennett • 1K'ay 18, 1964 , ' Page two Our studies have been pursued actively for several years, and we have made striking progress,, as noted below. The important point to cigarette companies is that ultimate success in such a cancer study would give the medical profession a tool to stimulate the body's resistance to all carcinogenic agents. When and if that occurs, the question of what is or is not a carcinogenic agent will assume less importance,, and emphasis will shift to preventing cancer regardless of' its cause. I should emphasize liere that our studies are not at all concerned -- pra or con- with the statistical approachh relating to tobacco or its con- stituents.. nE Doesn't Everybo. : Get Cancer?' We feel that far too little attention has been paid to why so many do not get cancer in proportion to those who do, in spite of the fact that every- one is constantly exposed to carcinogens -- chemicals, ionizing radiation,, viruses, etc. One of our recent visitors to this Institute, Dr. George R. Meneely, Professor of Nuclear Medicine of'the M. D~. Anderson Hospital and Tumor Institute at the University of Texas, aptly suuuned up our point of view. He wrote us that he had long entertained the notion that most researchers are barking,u.p the wrong,tree in looking for the causes of cancer. He adid.ed,"I think we ought to be looking for the cause of not havin cancer." Why, in other words, do so many people escape cancer even when they are continuously exposed to so many carcinogenic agents? Why, in fact, doesn't everyone get cancer? Does the fact that so many escape cancer despite continuous exposure to, carcinogenic agents (',e.g., ionizing radiation alone includes cosmic rays,, X-rays,, luminous watch dials, background radiation and even ultra violet)~ arise from their greater innate resistance to this formlof attack onithe human organism? If resistance of'all individuals can be.stimalated to cope better with carcinogens, a much broader method of avoiding,or curing cancer will be afforded. The attempt to avoid exposure to all carcinogenic agents is obviously hopeless. But the possibility of increasing resistance to such agents is very real. It is on that point of viewthat the work of this Institute in stimulating resistance!to cancer is based'. This approach appeared so promising that the,R'., J. Reynoldls Tobacco Company began contributing to the support off this Institute four years ago,, and has continued annually despite its heavy contributions to other research programs involving,a possible direct relationship between tobacco and cancer.

Mr. J. Edgar Bennett. May i8,, 1964 Page~three. What Resists Ca.ncer's. Gi-owtlii?' As indicated above, many provenicarcinogenic agents exist. Still others are suspected., Every living being,from the moment of birthi(and even before)iis conti:nu- ously exposed to the actionof such!carcinogenic agents. A!person off middle!age~has beenexposed countless times.. It is inconceivable.that none of these!exposures would result inia malig- nant mutation, i.e., cancer. Indeed, we !believe the formationof' malignant mutants tolbe a continuing process throughout life., However, not everybody gets cancer. In the.case of those!who donirt„ some- thing,must destroy the cell starting to undergo.malignant mutation., Thds is the host defense mechanism, expressed in great measure through action of the reticuloendothelial systemi(RES, for short) of the body. The fact that there is a host defense system~in individuals which combats malignancy is attested to by several well known phenomena. The same type of cancer grows at different rates in different persons. After surgery, cancer is often "quiescent" for severall years before it breaks loose again. Lastly, there are authenticated spontaneous cures of cancer in human beings -- not many, but enough to prove it a fact. S'i:nce resistance to cancer appears to involve the activity of'the reticulo- endothelial system, weakening,of'that systemishould and, indeed, does result in increased susceptibility to cancer. Strengthening,of that system should therefore result in decreased susceptibility to!cancer. That is why we feel that the greatest contribution to reducing,the toll of cancer will be the development of'an agent tolhelp the RES to prevent the onset of the disease. Or, if'it has begun, toiretard its growth or cure it. Can such an agent be found? We believe so,. Indeed, we believe we.havee found such a prototype chemical substance, one which has shown impressive activity against several types of'animal tumors in several species. Our fundamental approach appears tolbe in a very strong position. Our search for a stimulatory material led us by along and complex route to a lipid material available in significant amounts.inithe livers off certain species of'sharks. What We Have Accomplished in Cancer Researchi We have achieved success with.the.lipid from shark livers in stimulating,

Mr. J. Edgar Bennett May 18,, 1964 "Page four the reticuloendotYielial system to resist cancer in animals. The percentage of animals showing complete regression of malignant tumors in our original series of experiments has reached 50%. These experiments were done in a virus-produced tumor -- Rous sarcoma.. In another experiment the control group was given the virus which induces Rous sarcoma, while a test group was given the virus followed by two injec- tions of shark liver lipid, one dose after 7 days and one after 14 days. All animals iniboth groups developed tumors, but injection of'the shark liver lipid in the test group has been followed by a notable decrease in mortality, increase inisurvival time, and'regression: Average Survival Incidence Mortality Time of' of Tumors 80 Days Chickens that Die Regressions Control group ! (no shark liver lipid given after challenge) 100% 75% 31.3 days None Group given shark liver lipid 7 days and 1?+ days after challenge 100% 50% 45.5 days 43.1% In a parallel experiment with leukemia in mice induced by the Friend virus, favorable results have also been obtained. Injection of the shark liver lipid has greatly reduced the disease, as judged by splenomegaly, and sur- vival time has materially increased. For example, in a preliminary experi- ment ten mice were treated with shark liver lipid: and ten were treated only with the agent used for suspending,the lipid, e.g., glucose. The mice were then challenged with Friend virus. The lipid was given only once, 4-8'hours before challenge with the virus. Number of mice dead after indicated number of'weeks. Weeks 4 5 6 7 8 9 10 11 12 mice given lipid dead 0 0 0 0 1 1 2 3 3~ mice given glucose dead 1 1 1 3 3 4 7' 8 8 A non-virus-induced tumor,, Walker carcinoma, in rats is also under study at this Institute. In all, 100 animals wlth tumors have been studied thus far.. The rate of tumor "take" of Walker carcinoma is reduced in animals receiving, lipid. There were no:regressions inithe controls. In the treated groups we are running better than a 30% regressionlrate. Far larger series of' tests of these and other tumors, including spontaneous malignancies, are now under way.

M.V. J . Edgar Bennett. May 1i8', 1961+ ' Page five What Needs taBe Done Now in RES Cancer Researchi We have no doubt that the shark liver lipid is a useful agent inimice, rats and fowl challenged by certain cancers. Whether this will apply to all cancers in animals as well as cancer in man, we do:not know., We.havee ailong way to go and much research to do before finding,out, and before the results of our work can be used clinically. Developnment of an agent which helps the RES to resist cancer would obviously tend to bypass the problem of what causes a particular cancer or form of' cancer., Support of RES Cancer Studies A major foundation supporting our RES cancer research is the John A. Hartford Foundation. This is the ]largest foundation in the United States oriented almost entirely to medical research, and has an extensive staff of scientists who evaluate work done under its grants. It has increased its grant from $27,000 in 1963 to $49,800 in 1964 and has extended its annual grants through 1966. It also appropriated $25,500 for special equipment needed to expand this research. The Reynolds Bagley Verney Foundation, ~hich began to support our RES Cancer work in.1963, has given us an increase from $27,000 in 1963 to $1+0,200 for ]1964.$40,,200 is pledged'for 1965. There are categorical funds supporting our research on stimulationof'the reticuloend!othelial system to resist cancer.. The Fannie E'. R7ippel Foundation of'Newark also supports portions of this work at $24,1120 annually through 1965. More "General Fiznds" Needed Now Through the existing,categoricall grants mentioned above we are expanding the direct effort applied to RES cancer studies, as to the number of scientists involved, salaries, supp]1ies, etc., -- in other words, all direct costs. One large gap, however,, remains in our financial structure for attacking these vital problems, and it is that gap on which we seek added help. Increased categorical grants sometimes helg but more often do little to take care of the associated increment in general expenses. We are therefore faced with the necessity of increasing general funds from new~sources to match our increase in categorical funds. It is in this area of support of general funds that the R'.J. Reynold's Tobacco Company has aided our work materially, and which:IWLr. Ramm felt you might be willing to consider doing,for the P. Lorillard Co.

Mr., J. Edgar Bennett May 18, 1964 Page s i!x Will you therefore please consider this our formal application for a grant of general funds to this Institute? E'venia relatively small grant, say $5,000 to $10,000, will mean a great deal to us to defray the associated increment in general expenses.. We very much hope you will join R. J. Reynolds Tobacco C'ompany ini help- ing us to seek a solution to the cancer problem along,the lines we are. pursuing. We hold ourselves ready to give you any additional information you may want, or to welcome any qualified scientists you may wish to have visit us. Sincerely yours, John H. Heller, M.D. Executive Director JHH/bhr