Immunosuppression and Cancer
`
`By Israel Penn and Thomas E. Starzl
`
`BESIDES their beneficial eHect in retard(cid:173)
`
`ing or arresting the growth of certain
`types of neoplasms, a number of anticancer
`drugs may cause impairment of antibody
`synthesis and cell-mediated
`immunity.
`These
`immunosuppressive eHects have
`been used therapeutically to prevent and
`control rejection of organ homografts and
`also to treat a variety of clinical states.
`However, the anticancer agents have muta(cid:173)
`genic, teratogenic, and oncogenic properties
`in experimental animals and presumably
`also in humans. The present report is con(cid:173)
`cerned with their potential oncogenic ef(cid:173)
`fects in man.
`Evidence has been accumulated from
`three groups of patients about which full
`details are being published in Cancer. 1
`It should be emphasized that the vast ma(cid:173)
`jority of the cases have been contributed
`to us or have appeared in the literature
`and did not come from our own center.
`The groups include (1) immunosuppressed
`organ transplant recipients; (2) patients
`with a variety of noncancerous diseases
`treated with immunosuppressive agents;
`(3) Patients with malignant tumors who re(cid:173)
`ceived cancer chemotherapy.
`
`ORGAN TRANSPLANT RECIPIENTS
`Since 1968 we have maintained an infor(cid:173)
`mal Tumor Registry in Denver to record
`
`From the Department of Surgery, University of
`Colorado School of Medicine and the Veterans
`Administration Hospital, Denver, Colorado.
`Supported by research grants from the Veterans
`Administration, by grants RR-00051 and RR-00069
`from the General Clinical Research Centers pro(cid:173)
`gram of the Division of Research Resources,
`National Institutes of Health, and by grants
`AI-10176-01, AI-AM-08898, and AM-07772 of
`the United States Public Health Service.
`© 1973 by Grune & Stratton, Inc.
`
`cases of cancer in organ homograft recip(cid:173)
`ients.I-4 Tumors were encountered in three
`groups of transplant patients. (1)
`those
`which arose de novo after transplantation;
`(2) those inadvertently transmitted with
`the homograft; and (3) those which were
`present before transplantation.
`Cancers Which Appeared After Trans(cid:173)
`plantation: An organ transplant recipient
`maintained on chronic immunosuppressive
`therapy has a 5-6% chance of developing
`a de novo cancer within the first few years
`after transplantation. l -4 We have collected
`details of 122 such cases from transplant
`centers throughout the world. The patients
`had 125 tumors of which 76 were of
`epithelial origin (61%) and 49 (39%) were
`mesenchymal.
`The most common epithelial lesions were
`various skin cancers (27 cases, 36%), car(cid:173)
`cinomas of the cervix (11 cases, 14 %) and
`carcinomas of the lip (11 cases, 14 %). The
`remainder consisted of a wide variety of
`visceral carcinomas, many of high-grade
`malignancy.
`Forty-two (86%) of the 49 mesenchymal
`tumors were solid lymphomas, of which
`the most prominent subgroup was reticu(cid:173)
`lum cell sarcoma (30 cases, 61%). A most
`unusual feature of the lymphomas was
`their predeliction for the central nervous
`system which occurred in 20 of 41 cases
`(49%).
`The cancers occurred at an average age
`of 36 yr. The mean time of appearance of
`the tumors after transplantation was 28 mo
`(range 1-92 mo). The possibility of trans(cid:173)
`plantation of cancer from the donors was
`very small as only three of the 137 donors
`had tumors. Two of the three were cadaver
`donors who had medulloblastomas. The
`third donor, also a cadaver, had had a
`
`Transplantation Proceedings, Vol. V, No.1 (March), 1973
`
`943
`
`NOVARTIS EXHIBIT 2016
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 5
`
`

`

`944
`
`PENN AND STARZL
`
`carcinoma of the colon resected 5 yr previ(cid:173)
`ously and was apparently free of cancer at
`the time of donation. The recipients subse(cid:173)
`quently developed apparently unrelated
`cancers-reticulum cell sarcoma in two
`instances and a leiomyosarcoma in one.
`Almost all of the patients received immu(cid:173)
`no suppression with Azathioprine and pred(cid:173)
`nisone. Other immunosuppressive meas(cid:173)
`ures used were ALG (38), actinomycin
`(39), roentgen therapy to the homograft
`(45), splenectomy (41), thymectomy (7),
`thymic irradiation (2), thoracic duct lymph
`drainage (7), cyclophosphamide (3), endo(cid:173)
`lymphatic radiation (1), total body irradia(cid:173)
`tion (1), methotrexate (1), 6-mercapto(cid:173)
`purine (1), and azaserine (1).
`Treatment of the epithelial lesions of
`skin, lip, and uterine cervix followed con(cid:173)
`ventional lines and was usually successful.
`Other epithelial tumors had a worse prog(cid:173)
`nosis and in most instances either caused
`or contributed to the patients' deaths. The
`overall survival in patients with epithelial
`cancers was 44 of 74 (59%).
`The outlook for recipients with mesen(cid:173)
`chymal neoplasms was more gloomy as
`only 11 of 48 patients (23 %) are still
`living. Experience thus far is limited but it
`appears that conventional cancer therapy
`combined with reduction or cessation of
`immunosuppression may permit the pa(cid:173)
`tient's immune system to recover and resist
`the neoplasm. Five of the current survivors
`with highly malignant tumors were treated
`in this way with apparent eradication of
`the lesion and two more patients who died
`of infection or homograft failure were
`found to be free of cancer at autopsy.
`
`Transplanted Cancers
`
`Thirty-three patients received kidneys
`removed from donors who had cancer at
`the time of donation or who manifested
`evidence of the disease some months after(cid:173)
`ward. Subsequently, 19 recipients showed
`
`no evidence of tumor either at autopsy or
`during follow-up from 1-32 mo. Presuma(cid:173)
`.bly these last kidneys were either free of
`cancer or
`transplanted malignant cells
`failed to become established in the host.
`In four patients, tumor was found in
`homografts removed within the first 16
`days after transplantation. Two more recip(cid:173)
`ients developed involvement by cancer of
`the kidney and adjacent structures, while
`eight additional patients also had evidence
`of distant spread. Five of these last eight
`patients died of the transplanted cancer and
`in the remaining three patients immuno(cid:173)
`suppression was discontinued and the neo(cid:173)
`plasms apparently underwent
`rejection.
`One is still well 97 mo posttransplantation
`despite further immunosuppressive therapy
`given for two subsequent renal transplants
`each of which functioned for 12-18 mo.
`The other two patients died several months
`after cessation of immunosuppression and
`no tumor was present at autopsy.
`
`Cancers Which Were Present Before
`Transplantation
`
`Fifty-three organ recipients had cancers
`within the 5 yr preceding transplantation.
`In 14 instances the tumor did not involve
`the organ undergoing replacement; while
`in 39 cases transplantation was performed
`for treatment of cancer of one or both kid(cid:173)
`neys (21 cases), primary or metastatic can(cid:173)
`cer of the liver (17 cases), and carcinoma of
`the larynx (one case). When transplanta(cid:173)
`tion was performed in the treatment of
`cancer the neoplasm appeared to be local(cid:173)
`ized and resectable so that there was hope
`of obtaining a Ff cure."
`Of the 53 recipients, 28 (53%) had no
`evidence of tumor in follow-up of 2-42 mo.
`Twenty-two patients (41 %) developed re(cid:173)
`current or metastatic cancers, and three
`(6 %) developed de novo tumors of a type
`completely different from the original neo(cid:173)
`plasms.
`
`NOVARTIS EXHIBIT 2016
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 5
`
`

`

`MMUNOSUPPRESSION AND CANCER
`
`945
`
`PATIENTS WITH NONCANCEROUS
`DISEASES TREATED WITH
`IMMUNOSUPPRESSIVE AGENTS
`
`Thirty patients suffering from chronic
`cold hemagglutinin disease,
`rheumatoid
`arthritis, the nephrotic syndrome, systemic
`:upus erythematosus, ulcerative colitis, or
`;Jsoriasis were treated with immunosup(cid:173)
`~ressive agents and developed cancer. It
`~ight be argued that the immunosuppres(cid:173)
`sive agents played no role in the develop(cid:173)
`:nent of the tumors in many of these dis(cid:173)
`orders as they are autoimmune diseases in
`which an increased incidence of cancer has
`been reported. However,
`this argument
`does not apply to psoriasis which is not
`usually associated with cancer. The devel(cid:173)
`opment of cancer in 20 psoriatic patients
`chronically treated with methotrexate or
`aminopterin must, therefore, be regarded
`with the gravest suspicion.
`
`PATIENTS WITH CANCERS WHO
`RECEIVED CANCER CHEMOTHERAPY
`
`cancer
`received
`patients
`Sixty-one
`chemotherapy for one type of neoplasm
`and subsequently developed a new cancer
`of a different type. Were the anticancer
`drugs the cause of the tumors or could
`these have occurred spontaneously? It is
`well recognized that a patient with one type
`of cancer is more prone to develop a second
`neoplasm. Furthermore, certain tumor asso(cid:173)
`ciations are widely accepted such as the
`relationship between solid lymphoma and
`lymphocytic leukemia or the termination of
`chronic myelogenous
`leukemia in acute
`myeloblastic leukemia. A few of the 61
`cases may have been of this type. However,
`certain associations are decidedly uncom(cid:173)
`mon and raise the strong suspicion that the
`cancer chemotherapeutic agents, while con(cid:173)
`trolling the original neoplasm, may have
`contributed to the development of the sec(cid:173)
`ond type of tumor. A strikingly example
`was the development of acute leukemia in
`
`21 patients with multiple myeloma who
`were chronically treated with anticancer
`drugs, most commonly melphalan. Another
`is the development of a solid lymphoma in
`nine cases of chronic granulocytic leukemia.
`There are numerous additional cases in
`which a second tumor appeared while the
`patient was receiving chemotherapy for
`cancer. In many of these reports the au(cid:173)
`thors raised the question whether the sec(cid:173)
`ond neoplasm was induced by the very
`agent which had controlled the first cancer.
`
`DISCUSSION
`
`In animal studies numerous experiments
`have elicited the paradox that agents which
`can destroy or arrest the growth of cancer
`may themselves be oncogenic. Do the anti(cid:173)
`cancer and
`immunosuppressive agents
`cause cancer in man, and if so, by what
`mechanism? What is the effect of these
`agents on existing cancers?
`The answer to the first question is pro(cid:173)
`vided mainly by experience with organ
`homograft recipients. We have repeatedly
`reported a 5-6% incidence of de novo
`cancers
`in organ homograft
`recipients
`treated with chronic immunosuppressive
`therapy.l-4 These findings are reinforced
`by experience with neoplasms inadvertently
`transplanted with kidneys obtained from
`donors with cancer. It is very rarely pos(cid:173)
`sible to transplant cancer cells successfully.
`from one healthy human to another as they
`are recognized as "foreign" by the host's
`defenses and are readily destroyed. How(cid:173)
`ever, if the normal defense mechanisms
`are impaired by chronic immunosuppres(cid:173)
`sion, it is possible for the transferred malig(cid:173)
`nant cells to become established in the
`homograft, invade the surrounding tissues,
`and metastasize widely. If the immuno(cid:173)
`suppressive therapy is discontinued, the im(cid:173)
`mune defenses may recover and reject the
`cancer cells. This approach was successfully
`used in several cases reported in this paper.
`
`NOVARTIS EXHIBIT 2016
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 5
`
`

`

`946
`
`PENN AND STARZL
`
`Furthermore, it may also be applicable to
`the management of the more aggressive
`de novo tumors which arise posttransplan(cid:173)
`tation and which fail to respond to con(cid:173)
`ventional cancer therapy.
`The concept that tumors may arise in in(cid:173)
`dividuals under chronic immunosuppres(cid:173)
`sive therapy is further strengthened by
`reports concerning nontransplant patients
`treated with these agents. This applies par(cid:173)
`ticularly to sufferers from psoriasis who
`received chronic treatment with metho(cid:173)
`trexate or aminopterin.
`How do the immunosuppressive or can(cid:173)
`cer chemotherapeutic agents cause malig(cid:173)
`nant tumors? There are several possibili(cid:173)
`ties. First, the drugs may be directly on(cid:173)
`cogenic. Second, the compounds may po(cid:173)
`tentiate the effects of various environmen(cid:173)
`tal carcinogens such as tobacco, sunlight,
`or radiation. Third, the agents may cripple
`the surveillance function of the lympho(cid:173)
`reticular system by which potentially ma(cid:173)
`lignant mutant cells are normally elimi(cid:173)
`nated. Fourth, the weakened host defenses
`may permit oncogenic viruses to become
`established and cause malignant tumors.
`While there is unequivocal evidence that
`the anticancer and
`immunosuppressive
`agents may cause de novo neoplasms their
`effects on patients with preexisting tumors
`are not so clearly defined. In organ trans(cid:173)
`plant recipients with cancer there is a 41 %
`likelihood of recurrence or metastases of
`the original tumor and a 6 % incidence of
`unrelated de novo neoplasms. It is not
`possible. to determine whether the former
`figure is merely a reflection of the natural
`history of the cancers or is contributed to
`by chronic immunosuppressive therapy.
`In the case of advanced cancers treated
`with chemotherapy there are reports sug(cid:173)
`gesting that, while the original cancer had
`been controlled, the long-term chemother(cid:173)
`apy may have caused new cancers. No
`doubt there are numerous additional cases
`
`which have not been reported. The subject
`is a very complex one requiring considera(cid:173)
`tion of the increased likelihood of a patient
`with one cancer developing a second neo(cid:173)
`plasm; the tendency for one form of cancer
`to change to another related type; and
`the influence of other therapeutic agents,
`such as radiotherapy, which may be onco(cid:173)
`genic. In the present study the three most
`commonly used compounds were melpha(cid:173)
`lan, cyclophosphamide, and busulfan-all
`alkylating agents. These have radiomimetic
`actions and are known to be mutagenic
`and carcinogenic in laboratory animals.
`While cancer chemotherapy has had
`some notable successes, the overall results
`have been rather disappointing. These have
`been blamed on unresponsiveness of the
`tumor to a particular agent, or to the sub(cid:173)
`sequent development of resistance by the
`cancer cells, or to the toxic effects of the
`compounds used. Another factor, which
`has received relatively scant attention, is
`the prolonged immunosuppressive effect of
`the agents when administered continuously.
`Could this be the explanation for the ob(cid:173)
`servation that a better objective response
`and longer survival was observed when
`chemotherapy was given
`intermittently
`rather than continuously?
`The finding that cancer patients treated
`with chemotherapy may develop new
`tumors is more of academic than of prac(cid:173)
`tical importance and represents the price
`the patient has to pay for the hope of relief
`from the original cancer. Even so, several
`important lessons do emerge from this
`study. First,
`immunosuppressive agents
`should not be used in nonmalignant dis(cid:173)
`eases, such as psoriasis or rheumatoid ar(cid:173)
`thritis, unless all other forms of therapy
`have failed to provide relief. Second, in
`organ transplantation, donors with cancer
`should not be used except in cases with
`primary tumors of the central nervous sys(cid:173)
`tem which seldom spread to other organs.
`
`NOVARTIS EXHIBIT 2016
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 5
`
`

`

`IMMUNOSUPPRESSION AND CANCER
`
`947
`
`Third, when a cancer arises in an immuno(cid:173)
`suppressed patient it may be useful to
`withdraw or reduce the immunosuppressive
`therapy in the hope that the host defenses
`may recover and resist
`the neoplasm.
`
`Fourth, the studies emphasize the impor(cid:173)
`tance of the immune system in dealing with
`cancer and suggest that research on immu(cid:173)
`notherapy should be vigorously pursued.
`
`REFERENCES
`Transplant. Proc. 3:773, 1971.
`1. Penn, I., and Starzl, T. E.: Cancer. (In press).
`2. Penn, I.: Malignant Tumors in Organ Trans(cid:173)
`4. Starzl, T. E., Penn, I., Putnam, C. W., Groth,
`?lant Recipients. New York, Springer-Verlag, 1970.
`C. G., and Halgrimson, C. G.: Transplant. Rev.
`7:112, 1971.
`3. Penn~ I., Halgrimson, C. G., and Starzl, T. E.:
`
`NOVARTIS EXHIBIT 2016
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 5
`
`