1676
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Dec. 22, 1988
`
`PAN AMERICAN ALLERGY SOCIETY
`
`The 1989 training course and seminar will be held in San Antonio, Tex.,
`March 8-12.
`Contact Betty Kahler at the Society, 411 E. College, Fredericksburg, TX
`78624; or call (409) 297-5636.
`
`CHICAGO SCHOOL OF MEDICINE
`
`The following programs will be held: “The Psychiatric Interview” (Chicago,
`March 10-12); “New Techniques in ENT” (Vail, Colo., March 19-25); and
`“Advances in Gynecology” (Chicago, March 31-April 2).
`Contact Univ. of Chicago, Ctr. for Cont. Medical Educ., 5841 S. Maryland,
`Box 139, Chicago, IL 60637; or call (312) 702-1056.
`
`MIDWEST CENTER FOR OCCUPATIONAL HEALTH AND SAFETY
`
`The following courses will be offered in St. Paul, Minn.: “10th Annual Occu-
`pational Medicine Update” (March 10) and “Comprehensive Industrial Hygiene
`Review” (March 13-17, April 10-14, and Aug. 14-18).
`Contact Ruth K. McIntyre, MCOHS, St. Paul-Ramsey Medical Ctr., 640
`Jackson St., St. Paul, MN 55101; or call (612) 221-3992.
`
`ARIZONA CANCER CENTER
`
`The 7th winter symposium will take place in Snowbird, Utah, March 11-17.
`Contact Mary Humphrey, Arizona Cancer Ctr., Tucson, AZ 85724; orcall
`(602) 626-2276.
`
`PHARMACEUTICAL MANUFACTURERSASSOCIATION
`
`The 15th annual marketing section meeting, entitled “The Changing Landscape
`of American Medicine,” will be held in Laguna Niguel, Calif., March 12-15.
`Contact PMA, 1100 15th St., NW, Washington, DC 20005; or call (202) 835-
`
`JOHNS HOPKINS MEDICAL INSTITUTIONS
`
`The following courses will be offered in Baltimore, unless otherwise noted:
`“Spectrum of Developmental Disabilities Xi-Dyslexia: Clinical and Research
`Issues” (March 13-15); “PET: Imaging of Brain Chemistry with Special Empha-
`sis on PET as a Clinical Tool
`in Neurology, Psychiatry, and Neurosurgery”
`(March 16-18); “6th Annual Wilmer Institute Current Concepts in Ophthalmol-
`ogy” (Vail, Colo., March 18-25); “Retinal Vascular Center 19th Anniversary
`Meeting~Macula” (June 30); and “Diabetic Retinopathy in 1989” (Oct. 13).
`Contact Program Coordinator, Office of Cont. Educ., Johns Hopkins Medical
`Institutions, Turner 22, 720 Rutland Ave., Baltimore, MD 21205; or call (301)
`955-2959.
`
`UNIVERSITY OF UTAH
`
`The following courses will be offered: “Practices and Procedures in Asbestos
`Abatement for Contractors, Supervisors, Project Designers, and Workers” (Salt
`Lake City, March 13-16 and May 16-19; Denver, June 12-15; Aspen, Colo.,
`Aug. 21-24; and Las Vegas, Oct. 9-12); “Asbestos Refresher Course for Con-
`tractors, Supervisors, Project Designers, and Workers” (Salt Lake City, March
`17, June 23, and Oct. 20, and Aspen, Colo., Aug. 25); and “Comprehensive
`Review of Industrial Hygiene” (Maui, Hawaii, March 20-24).
`Contact RMCOEH/Cont. Educ., Univ. of Utah, Bldg. 512, Salt Lake City, UT
`84112; or call (801) 581-5710.
`
`NEUROLOGYIN THE 1990’s
`
`The continuing education and board review course will be offered in Cam-
`bridge, Mass., March 13-18.
`Contact Dr. Neil W. Kowall, Neurology Service, Massachusetts General
`Hosp., Fruit St., Boston, MA 02114; or call (617) 726-3786.
`
`INTERNATIONAL CLINICAL HYPERTHERMIA SOCIETY
`
`The 12th international symposium will take place in Rome, April 27-30.
`Contact Clinica Chirurgica, II-Univ. di Roma, Ospedale S. Eugenio, 10 Piaz-
`zale Umanesimo, 00144 Rome,Italy; or call (39) 6 59-23-968.
`
`SPECIAL REPORT
`
`USE OF TUMOR-INFILTRATING
`LYMPHOCYTES AND INTERLEUKIN-2 IN
`THE IMMUNOTHERAPYOF PATIENTS
`WITH METASTATIC MELANOMA
`
`A Preliminary Report
`
`STEVEN A. RosENBERG, M.D., Pu.D.,
`BeEver_LyS. Packarp, Pu.D.,
`PauM. AEBERSOLD, Pu.D., Diane Sotomon, M.D.,
`Suzanne L, Topauian, M.D.,
`STEPHEN T. Toy, Pu.D., Paut Simon, Pu.D.,
`Micnuaet T. Lotze, M.D., James C. Yanc, M.D.,
`Cviaupta A. Seipp, R.N., CoLLEEN Simpson, R.N.,
`CHARLES CarTER, STEVEN Bock, M.D.,
`Douctas SCHWARTZENTRUBER, M.D.,
`Joun P. Wei, M.D., anp Donatp E. Wuirte, M.S.
`
`Abstract Lymphocytes extracted from freshly resected
`melanomas can be expandedin vitro and can often medi-
`ate specific lysis of autologous tumorcells but not alloge-
`neic tumor or autologous normalcells. We treated 20 pa-
`tients with metastatic melanoma by means of adoptive
`transfer of these tumor-infiltrating lymphocytes and inter-
`leukin-2, after the patients had received a single intrave-
`nous dose of cyclophosphamide. Objective regression of
`the cancer was observed in 9 of 15 patients (60 percent)
`whohad not previously been treated with interleukin-2 and
`in 2 of 5 patients (40 percent) in whom previous therapy
`with interleukin-2 had failed. Regression of cancer oc-
`curred in the lungs,liver, bone, skin, and subcutaneous
`sites and lasted from 2 to more than 13 months. Toxic
`effects of interleukin-2 occurred, although the treatment
`course was short (five days); these side effects were
`reversible.
`It appears that in patients with metastatic melanoma,
`this experimental treatment regimen can produce higher
`responserates than those achieved with interleukin-2 ad-
`ministered alone or with lymphokine-activated killer cells.
`It is too early to determine whetherthis new form of immu-
`notherapy can improve survival, but further trials seem
`warranted.
`
`WEhavepreviously reported that adoptive immu-
`notherapy using lymphokine-activated killer (LAK)
`cells plus interleukin-2 or high-dose interleukin-
`2 alone can result
`in the regression of cancer in
`a variety of murine models'* andin selected patients
`with advanced metastatic cancer.’ The LAK cells
`used in this therapy were non-T, non-B, “null” lym-
`phocytes capable of recognizing and lysing a wide
`variety of fresh tumor cells but not normal
`target
`cells.'>° The ability of LAK cells to mediate tumor
`
`From the Surgery Branch (S.A.R., B.S.P., P.M.A., S.L.T., M.T.L., J.C.Y.,
`C.A.S., C.S., $.B., D.S., J.P.W., D.E.W.) and the Laboratory of Pathology
`(D. Solomon), National Cancer Institute, and the Department of Transfusion
`Medicine (C.C.), Clinical Center, National Institutes of Health, Bethesda, Md.;
`and E.I. DuPont and Company (S.T.T., P.S.), Glenolden Laboratories, Wil-
`mington, Del. Address reprint requests to Dr. Rosenberg at the National Cancer
`Institute, 9000 Rockville Pike, Bethesda, MD 20892.
`
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`

`Vol. 319 No. 25
`
`SPECIAL REPORT
`
`1677
`
`regression led us to search for other subpopulations
`of lymphocytes that might be effective in cancer
`treatment.
`Wepreviously described a technique for the isola-
`tion and in vitro expansion of lymphocytesinfiltrating
`into solid tumor masses.'° The adoptive transfer of
`these tumor-infiltrating lymphocytes (TIL) was from
`50 to 100 times more potent than that of LAK cells
`in mediating the regression of established cancer
`in several murine tumor models.'':!? Successful ther-
`apy with TIL depended on pretreatment of the tu-
`mor-bearing host with either cyclophosphamide or
`total-body irradiation and on the simultaneous ad-
`ministration of interleukin-2.'!' TIL can be grown
`from a variety of human cancers.'*!9 In a Phase I
`study of 12 patients treated either without cyclo-
`phosphamide or with escalating doses of the drug,
`with escalating doses of interleukin-2, and with low
`numbers of TIL, we demonstrated the safety of the
`administration of this combination therapy.2° In
`another pilot study,
`treatment with low numbers
`of TIL without cyclophosphamide or interleukin-2
`was also safe, although no objective antitumor re-
`sponses were seen.2! We present our preliminary
`results of the treatment of a series of patients with
`metastatic melanoma by means of a regimen of cy-
`clophosphamide in conjunction with the adoptive
`transfer of large numbers of autologous TIL andinter-
`leukin-2.
`
`Patients
`
`METHODS
`
`All the patients had a diagnosis of metastatic malignant melano-
`ma, which could be evaluated by physical or radiographic examina-
`tion. Of the 20 patients in this study, 18 had undergone surgical
`excision, 5 had received chemotherapy that had failed, 3 had re-
`ceived radiotherapy, 5 had received therapy with interleukin-2, and
`1 had received therapy with alfa-interferon. None had undergone
`any other form of therapy for their disease for 30 days before treat-
`mentaccordingto our protocol, and none received treatment during
`the follow-up period. Patients with central nervous system metasta-
`ses were excluded; however, metastases to the brain developed in
`three patients (not included in this study) between the time of tumor
`resection and the growth of the TIL and weretreated with reduced
`doses ofinterleukin-2.
`
`Protocol
`
`Tumor deposits were resected, usually under local anesthesia;
`most resected tumors weighed between 10: and 30 g. TIL were
`expandedin culture for four to eight weeks, according to techniques
`similar to those previously described.’ When the TIL were ready
`for infusion, patients first received a single intravenous: dose of
`cyclophosphamide (25 mg per kilogram of body weight) and 36
`hours later the first intravenous infusion of TIL in an intensive
`care unit; a maximum of 2X10"! cells were administered in 200 to
`250 ml over a period of 30 to 60 minutes. Each patient received
`a total of one to seven infusions over one to two days, depending
`on the numberofcells to be administered and the time required to
`harvest
`the cells. After the first
`infusion of TIL,
`the patients
`began receiving recombinantinterleukin-2 (kindly supplied by the
`Cetus Corporation, Emeryville, Calif.) (100,000 units per kilogram,
`given intravenously every eight hours in 50 ml of 0.9 percent sa-
`line with 5 percent albumin).?? Interleukin-2 was administered
`until dose-limiting toxicity occurred; some doses were omitted
`depending on the patient’s tolerance. Theside effects of interleu-
`
`kin-2 administration were treated with acetaminophen, indometha-
`cin, ranitidine, and meperidine as previously described.’
`
`Assessment of Response to Treatment
`
`A response wasconsidered to be completeifall measurable tumor
`disappeared, and to be partial if the sum of the products of the
`longest perpendicular diameters ofall lesions decreased byat least
`50 percent and if no tumor had any increase and no new tumor
`appeared. The term “objective responses” refers to the sum of com-
`plete and partial responses.
`
`REsULTS
`
`Studies in murine tumor models have indicated
`that successful therapy with TIL depended onprior
`administration of cyclophosphamide.'! Thus, to de-
`termine the degree of tolerance and responseto cyclo-
`phosphamideplus interleukin-2 without administra-
`tion of TIL, we begantheseclinical studies by treating
`a series of 13 patients with metastatic melanomawith
`various doses of cyclophosphamide (4 patients with
`50 mg per kilogram, 6 with 25 mgper kilogram, and
`3 with 10 mg per kilogram)followed 36 hours later by
`infusion of interleukin-2 (100,000 units per kilogram
`every eight hours). On the basis of this preliminary
`evaluation, a dose of 25 mg per kilogram wasselected
`for the TIL therapy because it was the highest dose
`that resulted in acceptable levels of hematologic
`suppression when given with interleukin-2. Partial
`responses were observed in 2 of the 13 patients
`(1 patient who received 50 mg per kilogram and
`1 who received 10 mg per kilogram) — results sim-
`ilar to those expected using treatment with inter-
`leukin-2 alone.
`The characteristics of the 20 patients with metastat-
`ic melanoma treated with cyclophosphamide, TIL,
`and interleukin-2 and the characteristics of their treat-
`ment and response are shown in Table 1. The number
`of TIL infused ranged from 3X10!° to 75x10!°
`cells (median, 20.5 10!®; 25th percentile, 12.8 10!°;
`75th percentile, 29.8x10'°). Of the 15 patients who
`had never before been treated with interleukin-2, 9
`(60 percent) had objective evidence of cancer regres-
`sion. Ofthe five patients in whom interleukin-2—based
`therapies had previously failed, two (40 percent) had
`objective responses. Regression of cancer was ob-
`served at a variety of sites,
`including the lungs
`(Fig. 1), liver, spleen, lymph node, bone, and subcuta-
`neous tissue. Two of these responding patients (Pa-
`tients 8 and 9) received a second course of therapy
`with cyclophosphamide, TIL, and interleukin-2, and
`four (Patients 3 through 6) received a second course
`of interleukin-2 alone approximately two months
`after the first course of cyclophosphamide, TIL, and
`interleukin-2. All these patients, however, had objec-
`tive responsesafter the first course of treatment. The
`duration of the responses ranged from 2 to more than
`13 months.
`Thetoxicity of the treatment is summarized in Ta-
`ble 2. Chills were the only toxic effect associated with
`TIL infusion and were easily controlled with meperi-
`dine. Mosttoxic effects were attributable to the inter-
`
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`

`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Dec. 22, 1988
`
`Table 1. Characteristics of Therapy in 20 Patients Treated with TIL.*
`PATIENT
`Dosks OF
`No
`IL. 2t
`
`Sex/AGE
`
`Tumor HARVEST
`
`%
`LYMPHO-
`CYTES
`
`15
`70
`6
`
`6
`16
`28
`
`41
`4
`
`24
`50
`
`SITE
`
`Subcutaneous
`Subcutaneous
`Subcutaneous
`
`Subcutaneous
`Lymph node
`Subcutaneous
`
`Lymph node
`Lymph node
`
`Liver
`Lymph node
`
`DAYS
`IN
`CULTURE
`
`27
`29
`27
`
`24, 38
`29
`34
`
`39
`42
`
`26
`56
`
`1
`2
`3
`
`4
`5
`6
`
`7
`8
`
`9
`10
`
`F/46
`M/S6
`F/42
`
`F/38
`M/37
`M/21
`
`M/S8
`M/25
`
`M/58
`F/45
`
`IL
`12
`13
`14
`
`F/28
`M/S9
`M/S0
`M/35
`
`6
`6
`7
`6
`
`29
`53
`44
`33
`
`TUMOR-INFILTRATING LYMPHOCYTES*
`LYMPHOCYTE,
`CELLS
`EXPANSION
`INFUSED
`INDEX
`(x197!°)
`
`=CD3/CD4/CD8
`(%)
`
`330
`300
`4,633
`
`27,100
`585
`2,423
`
`588
`44,450
`
`2.317
`1,802
`
`23
`3
`25
`
`30
`9
`23
`
`1.3
`19
`
`75
`12
`
`95/6/93
`74/4164
`97/83/12
`
`98/82/20
`98/8 1/7
`83/93/10
`
`99/98/<3
`97/19/>90
`
`98/88/<3
`93/87/3
`
`4,867
`2,623
`2,443
`32,017
`
`35
`17
`43
`29
`
`99/93/3
`96/67/2
`76/73/11
`95/80/14
`
`RESPONSE
`
`TYPE
`
`Partial
`Complete
`Partial
`
`Partial
`Partial
`Partial
`
`None
`Partial
`
`Partial
`Mixed
`
`1
`12
`7
`
`7
`7
`13
`
`12
`13
`
`7
`10
`
`14
`9
`6
`10
`
`None
`None
`None
`Partial
`
`SITE,
`
`Lung
`Subcutaneous
`Lung, subcutaneous,
`nodal
`Lung, subcutaneous
`Subcutaneous
`Liver, spleen, nodal,
`subcutaneous
`
`—
`Lung, liver, nodal,
`subcutancous
`Lung, liver
`Liver responded
`(brain metastases)
`
`—
`—
`—_—
`Lung, bone,
`subcutaneous
`
`DURATION
`(mo)
`
`3
`>13
`3
`
`4
`7
`7
`
`—
`9
`4
`—_—
`—
`
`—
`
`—
`4
`
`Subcutaneous
`Soft tissue
`Soft tissue
`Bone andsoft
`tissue
`—
`—
`None
`7
`100/50/50
`22
`17,544
`30
`84
`Lymph node
`F/S0
`1S
`—
`—
`None
`4
`95/20/70
`10
`45,597,875
`49
`15
`Lymph node
`M/32
`16¢
`—
`—
`None
`3
`95/2/80
`15
`7,062
`37
`58
`Subcutaneous
`M/41
`17
`2
`Subcutaneous
`Partial
`ll
`100/15/85
`19
`39,827
`39
`10
`Subcutaneous
`F/39
`igt
`—
`—
`None
`8
`98/72/16
`34
`8,938
`36
`18
`Lung
`F/35
`19¢
`
`
`
`
`
`
`
`
`
`
`
`F/S8 Lymph node 21 31 45,670 17 100/98/4 3 Partial Nodal20 6
`
`*Before treatment with TIL, all patients received 25 mg of cyclophosphamide per kilogram.
`+Doses of 100,000 units per kilogram every eight hours. Patient 16 received three ofthe four doses at 30,000 units per kilogram, Patient 17 receivedall three doses at 30,000units per kilogram
`Previous treatment with interleukin-2 alone or interleukin-2 plus LAK cells had failed.
`
`leukin-2 infusions and appeared to be related to an
`increased vascular permeability that led to loss of
`intravascular volume and accumulation of fluid in
`visceral organs and soft
`tissues.”*> No patient died
`of treatment. The side effects all resolved after in-
`terleukin-2 was discontinued, and the median time
`from the end of treatment to hospital discharge was
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`four days (25th percentile, three days; 75th percentile,
`seven days). Toxicity was lower in this regimen than
`in others using this dose of interleukin-2, because the
`treatment time was shorter (median, 5 days; 25th per-
`centile, 4 days; 75th percentile, 6 days) than the 15
`days required for a course of therapy with LAK cells
`plus interleukin-2.
`
`
`
`
`
`
`10-22-87
`
`Figure 1.
`Pulmonary Metastasesin Patient 4 before (Left) and after (Right) One Course of TIL, Interleukin-2, and Cyclophosphamide.
`The later chest film shows regression of the metastases. Multiple subcutaneous metastases regressed completely as well.
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`Vol. 319 No. 25
`
`SPECIAL REPORT
`
`1679
`
`Tumorcells were obtained from 17 patients (other
`than the 20 patients listed in Table 1), but no treat-
`ment was given to them — 7 patients because of de-
`bilitation caused by the progression of their disease,
`8 because of poor lymphocyte growth, and 2 because
`of contamination of cultures by bacteria. Three other
`patients not listed in Table 1 had brain metastases
`that developed between the time of tumor harvest and
`the time of final TIL growth; they received TIL, but
`because of their poor performancestatusat the time of
`treatment their doses of interleukin-2 were reduced.
`One of these patients died 13 days after infusion of
`TIL, with metastases involving the brain andvirtually
`all visceral organs. Another patient had a decrease in
`cutaneous metastases and a decrease in brain metasta-
`ses on CT scans obtained one month after treatment.
`This patient died at home one month later of what
`appeared to be an intracerebral event, although no
`autopsy was performed.
`
`DIscussION
`
`Conventional chemotherapyis relatively ineffective
`in the treatment of patients with metastatic melano-
`ma, and approximately 6000 patients die of this dis-
`ease in the United States each year. We have sought
`new immunotherapeutic approaches to the treatment
`of patients with melanoma and have reported that
`regression of metastatic melanoma could be achieved
`in some patients treated with high doses of interleu-
`kin-2 alone or in combination with the adoptive trans-
`fer of LAKcells.*’ A recent analysis of our experience
`(as of May 1988) has revealed that objective evidence
`of cancer remission was observedin 10 of 48 patients
`(21 percent; 4 with complete and 6 with partial regres-
`sions) in whom melanomawastreated with LAKcells
`plus interleukin-2 and in 9 of 37 patients (24 percent;
`all 9 with partial regressions) treated with high doses
`of interleukin-2 alone.
`Studies of the adoptive transfer of TIL in murine
`tumor models have shownthat these cells are 50 to
`100 times more effective than LAK cells in mediat-
`ing tumor regression.'!'? In contrast to LAK cells,
`TIL obtained from mice and patients are predomi-
`nantly T lymphocytes, and those from patients are
`often capable of lysing autologous melanoma in
`a fashion that is highly specific and restricted by
`the major histocompatibility complex.'*!° As with
`other forms of experimental adoptive therapy with
`T cells,
`immunosuppression of the tumor-bearing
`host with either cyclophosphamideor total-body ir-
`radiation is
`required for
`treatment
`to be success-
`ful.2*© This pretreatment
`is
`thought
`to eliminate
`suppressorcells or to facilitate lymphocyte “homing.”
`Cyclophosphamide administration or total-body irra-
`diation does not affect treatment with LAK cells in
`murine models.
`Wethereforefirst treated 13 patients with the com-
`bined administration of cyclophosphamide and inter-
`leukin-2, and observed only two objective responses
`(15 percent),
`in accord with the response expected
`
`with the use of interleukin-2 alone. However, the addi-
`tion of TIL to the combination of cyclophosphamide
`and interleukin-2 resulted in responses in 9 of 15
`patients (60 percent) who had not previously been
`treated with interleukin-2 and in 2 of 5 patients
`(40 percent) in whom treatment with interleukin-2
`had previously failed (both patients had previously
`received a different preparation of recombinantinter-
`leukin-2). It thus appears that treatment with TIL
`increased response rates among patients with meta-
`static melanoma, as compared with therapy with
`LAKcells and interleukin-2, cyclophosphamide and
`interleukin-2, or interleukin-2 alone. It should be em-
`phasized, however, that the duration of response was
`often short, and it is too early to determine the effect
`of treatment on survival. The results reported here
`reflect primarily the results of a single cycle of treat-
`ment with TIL. Since only | of the 11 responding
`
`Table 2. Toxicity of Treatment with TIL, Interleu-
`kin-2, and Cyclophosphamide.
`No. OF
`PATIENTS
`(N = 20)
`
`Toxic EFFECT
`
`Chills
`Nausea and vomiting
`Diarrhea
`Mucositis
`Hyperbilirubinemia (peak value)*
`2.1-6.0 mg/dl
`6.1—10.0 mg/dl
`210.0 mg/dl
`Hypotension (requiring pressors)
`Arrhythmias
`Oliguria
`<80 ml/8 hr
`<240 ml/24 hr
`Elevated creatinine (peak value)t
`2.1-6.0 mg/dl
`6.1—10.0 mg/dl
`210.0 mg/dl
`Weight gain (% body weight)
`5.1-10.0
`10.1-15.0
`215.1
`Respiratory distress
`No intubation
`Intubation
`Anemia requiring transfusion (units transfused)
`1-5
`6-10
`211
`
`10
`11
`9
`1
`
`10
`10
`0
`13
`1
`
`10
`0
`
`8
`2
`0
`
`5
`2
`2
`
`1
`I
`
`14
`2
`0
`
`4
`7
`6
`
`Thrombocytopenia (minimum/mm?)
`20,000
`21,000—60,000
`61,000- 100,000
`Neutropenia (minimum/mm?)
`1
`=500
`3
`501-1000
`4
`Disorientation
`1
`Coma
`Somnolence
`1
`Death
`0
`
`
`*Bilirubin levels returned to normalin all patients over a median of
`4.5 days.
`tCreatinine levels retumed to normal in all patients over a median of
`8.5 days.
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`Miltenyi v. UPenn
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`1680
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Dec. 22, 1988
`
`patients had a complete response, perhaps more inten-
`sive or repeated therapy might improve the quality of
`response.
`The shorter course of treatment with TIL and inter-
`leukin-2 (5 days as compared with 15 days for therapy
`with LAKcells and interleukin-2) wasbetter tolerated
`by the patients. There were no treatment-related
`deaths amongthe20 patients described here, although
`1 of 3 patients with brain metastases treated with low-
`er doses of interleukin-2 died 13 days after therapy,
`with extensive intracranial, visceral, and cutaneous
`disease. All side effects occurring in these 20 patients
`resolved after the completion of therapy.
`Extensive immunologic studies have been per-
`formed on theinitial suspensions of tumorcells and on
`the infused TIL to determine the requirements for
`successful therapy. The great majority of the infused
`TIL were CD3+,
`though the relative number of
`CD4+ and CD8+ cells varied among the patients
`(Table 1). Cultures of TIL exhibited varying patterns
`of cytotoxicity, proliferation, and lymphokine produc-
`tion, though nopattern has yet emerged to predict the
`TIL populations that will mediate cancer regression
`in vivo. Interestingly, a study of TIL traffic in six
`patients with melanoma who each received a small
`aliquot of indium-111-labeled TIL revealed substan-
`tial homing of TIL to cancer deposits.”’
`This study represents a further developmentof the
`approach of adoptive immunotherapy to the treat-
`ment of patients with advanced cancer. Higher re-
`sponserates have been achieved using TIL in patients
`with metastatic melanomathan havepreviously been
`achieved with treatment with LAKcells, and patients
`with other types of cancer should be studied. Al-
`thoughthe treatmentcan causeregression of cancer,it
`is not yet known whetherregression will affect surviv-
`al. In addition, the methods required to generate TIL
`are complex and laborious, and simplification of the
`culture techniques is required. This treatment should
`be considered highly experimental and should be pur-
`sued in centers where the immunologic factors re-
`quired for successful treatment can be assessed. The
`present study does demonstrate, however, that the
`adoptive transfer of immune autologous cells can
`be effective in mediating cancer regression in selected
`patients, and further emphasizes the need to pursue
`the developmentof this biologic approach to cancer
`therapy.
`Weare indebted to Deborah Shulman, Carolyn Buresh, Linda
`Paczkowski, Cornelia Hyatt, Susan Johnson, and Kathryn
`Ottaway, who generated the TIL cells; to data managers Melissa
`Corbitt and Allison McMullen; and to the dedicated nurses of the
`2 East Surgical Unit and the 2J Surgical Intensive Care Unit of the
`Clinical Center, National Institutes of Health, who provided the
`patients with excellent and compassionatecare.
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`UPenn Ex. 2031
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