Principles and Practice of·
`
`nco ogy
`
`Derek Raghavan, MBBS, PhD, FRACP, FACP
`Chief, Departments of Solid Tumor Oncology
`and Investigational Therapeutics
`Roswell Park Cancer Institute and
`Professor of Medicine and Urology
`State University of New York at Buffalo
`Buffalo, New York
`
`Howard I. Scher, MD
`Chief, Genitourinary Oncology Service
`Associate .Attending Physician
`Division of Solid Tumor Oncology
`Department of Medicine
`Memorial Sloan-Kettering Cancer Center
`New York, New York
`
`Steven A. Leibel, MD
`Vice Chairman and Clinical Director
`Attending Radiation Oncologist
`Department of Radiation Oncology
`Memorial Sloan-Kettering Cancer Center
`New York, New York
`
`Paul Lange, MD, FACS
`Professor and Chair .
`Department of Urology
`University of Washington
`Seattle, Washington
`
`With 226 Additional Contributors
`
`r Lippincott - Raven
`
`_ , P U B L
`
`I S H E R S
`
`Philadelphia • New York
`
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`

`- 1
`
`Developmental Editor: Eileen Wolfberg Jackson
`Project Editor: EUen M. Campbell
`Production Manager. C11TCn Erlichman
`Production Coordinator: MaryClare Malady
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`Indexer. Steve Sorenson
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`Primer: Courier Book Company/Westford
`
`Copyright Cl I 997 by Lippincott-Raven Publishm. All rights reserved. This book is
`protected by copyright. No pan of it may be reproduced, stored in a retrieval system,
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`
`Materials appearing in this book prepareed by individuals as part of their official duties
`as U.S. Gov~ent employees are not covered by the above-mentioned copyright.
`
`Library of Congress Cataloging-in-Publication Data
`Principles and practice of genitourinary oncology I Derek Raghavan ...
`[et al.] ; with 226 additional contributors.
`p. cm.
`Includes bibliographical references and index.
`ISBN 0-397-51458-1 (alk. paper)
`I. Raghavan, Derek.
`I. Genitourinary organs- Cancer.
`I. Urogenital Neoplasms. WJ 160 P9573 1996)
`(DNLM:
`RC280.U74P746 1996
`616.99'26-dc20
`DNLM/DLC
`for Library of Congress
`
`96-8893
`CIP
`
`Care has been taken to confirm the accuracy of the information presented and 10
`describe generally accepted practices. However, the authors, editors, and publisher are
`not responsible for errors or omissions or for any consequences from application of the
`information in ibis book and make no warranty, express or implied, with respect to the
`contents of the publication.
`The authors, editors, and publisher have exerted every effort t.o ensure that drug
`selection and dosage set forth in this text are in accordance with current
`recommendations and prac1ice at the time of publication. However, in view of ongoing
`research, changes in government regulations, and the constant flow of information
`relating to drug therapy and drug reactions, the reader is urged to check the package
`insert for each drug for any change in indications and dosage and for added warnings
`and precautions. Th.is is panicularly imponant when the recommended ageot is a new
`or infrequently employed drug.
`Some drugs and medical devices presented in this publication have Food and Drug
`Administration (FDA) clearance for limited use in restricted research settings. It is the
`responsibility of the health care provider to ascertain the FDA status of each drug or
`device planned for use in their clinical practice.
`
`9 8 7 6 5 4 3 2 I
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`Principles and Practice of Gem"tourinary Oncology, edited by
`Derek Raghavan, Howard I. Scher, Steven A. Leibel and Paul H.
`Lange. Lippincott-Raven Publishers, Philadelphia, f:J
`l997.
`
`0
`
`CHAPTER 84
`
`Systemic Immunotherapy for Genitourinary
`Neoplasms
`
`Mitchell H. Sokoloff, Robert A. Figlin, Jean B. ·de Kernion,
`and Arie S. Belldegrun
`
`I
`
`.1
`
`Despite advances in prevention and early detection, refinement
`in surgical technique, and improvements in adjuvant radio- and
`chemotherapy, the ability to cure cancer remains elusive in
`many patients. The continuing challenge of cancer treatment is
`the successful management and eradication of metastatic dis(cid:173)
`ease. Over the past decade, it has become increasingly apparent
`that effector cells of the immune system play an important role
`in the recognition and elimination of neoplastic cells. Recently,
`therefore, cancer therapies have been directed at modulating
`and exploiting the components of the immune system. Specific
`molecules (i.e., cytokines) have been targeted because of their
`involvement in the initiation and maintenance of immu.ne sur(cid:173)
`veillance and response. Early clinical studies with systeinie cy(cid:173)
`tokine infusions demonstrated tumor regression, but usually at
`the cost of substantial toxicity and side effects. Refinements
`have included the concept of adoptive immunotherapy using
`lymphokine-activated killer (LAK) and tumor-infiltrating lym(cid:173)
`phocyte (TIL) cells, with·1:he. intent to increase the amount of
`tumor regression while reducing toxicity. Current research fo(cid:173)
`cuses on utilizing gene therapy as a mechanism by which the
`immune response to neoplastic tissue can be modulated and
`improved.
`Renal cell carcinoma and bladder cancer are prime examples
`of diseases where immunotherapy holds promise for achieving
`improved cure rates. Metastatic renal cell carcinoma has a poor
`prognosis, with an average survival of only 6 to 12 months from
`the time of diagnosis. Recent developments in immunotherapy,
`however, have resulted in an improved outlook. The incidence
`of bladder cancer is on the rise, yet the mortality peaked in the
`mid 1980s and continues to decline. Nonetheless, the number of
`patients with recurrent or progressing superficiai bladder tumors
`after treatment with transurethral resection and established in(cid:173)
`travesical chemotherapy protocols remains at 50% of those
`treated. It is in this patient population where innovation in tradi(cid:173)
`tional treatment methods is most needed and immunotherapy
`can fill the void. Investigations into applying immuno- and gene
`therapy for the treatment of meta~tatic prostate cancer have
`been initiated, and early results ap~ear promising (although it
`is too soon for definitive conclusions).
`
`This chapter explores the role of immunotherapy in the treat(cid:173)
`ment of advanced genitourinary neoplasms. Principles of immu(cid:173)
`notherapy will be discussed, along with reviews of the most
`current immunotherapeutic applications to the treatment of
`renal cell, bladder, and prostate cancers. Future treatment mo(cid:173)
`dalities will also be outlined.
`
`OVERVIEW: HUMORAL AND CELLULAR
`IMMUNOLOGIC EFFECTOR CELLS*
`
`Although immune responses have traditionally been divided
`into two categories-humoral, mediated by antibody-secreting
`B-lymphocytes, and cellular, mediated by T-lympho(cid:173)
`cytes-they involve interactions from both cell types, with ad(cid:173)
`ditional support from a third, the antigen-presenting cell (APC).
`After initial MHC-restricted activation by APCs, T-lympho(cid:173)
`cytes act through either direct contact with target cells, or via
`secreted cytokines, agents that augment target c~ll behavior
`through a variety of mechanisms.
`Initially, T-lymphocytes were divided into T8 (CDS+) and
`T4 (CD4+) elements, based on specific surface molecules that
`appeared to influence their behavior. CDS+ cells were deter(cid:173)
`mined to be cytotoxic, and were therefore named cytolytic T
`lymphocytes. They secrete a limited spectrum of cytokines,
`such an interleukin 3 (IL3), interferon y (IFN y), and granulo(cid:173)
`cyte-monocyte colony-stimulating factor (GM-CSF). CD4+
`elements can now be further divided functionally, by the cyto(cid:173)
`kines they secrete, into Th 1 cells, which prodµce IL2, IL3, IFN y,
`lymphotoxin, and GM-CSF, and Th2 , which produce GM-CSF,
`IL3, IL4, ILS, IL6, and ILIO. These cytokines have widespread
`effects on APCs, B lymphocytes, and other T lymphocytes, and
`are discussed later in this chapter.
`Once activated by anti~en, cytokines, or APCs, B lympho-
`
`*For a thorough review of the principles of immunology, please refer
`to William Paul's text Fundamental Immunology. (New York: Raven Press,
`1993).
`
`869
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`870
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`I CHAPTER 84
`
`cytes proliferate into plasma cells, which subsequently produce
`antibodies. ''Monoclonal antibodies'' are laboratory-designed
`antibodies produced with specific characteristics and in higl)
`quantity. They have come to play ·a significant role in medical
`research. Currently, however, monoclonal antibodies have had
`little utility in the treatment of genitourinary neoplasms. When
`renal, prostate, or bladder tumor-specific pepti4es can be identi(cid:173)
`fied, isolated, and characterized, monoclonal antibodies to that
`antigen can be produced, attached to cytotoxic agents, and per(cid:173)
`haps used to directly target and destroy those tumor cells. At
`this time, however, this is mostly conjecture. T lymphocytes,
`on the other hand, maintain a primary role in current immuno(cid:173)
`therapeutic protocols for advanced genitourinary cancers, and
`will be discussed further throughout this chapter.
`
`FUNDAMENTALS OF IMMUNOTHERAPY
`
`The immune system contributes to the ~urveillance and de(cid:173)
`struction of tumor cells. 1 Multiple cellular and humoral immune
`effectors inhibit tumor proliferation. Cellular mediators with
`antitumor activity killer (MHC-restricted cytotoxic T cells (Tc),
`natural killer (NK) cells, and lymphokine-activated killer
`(LAK) cells. The goal of immunotherapy in the treatment of
`advanced cancers is to sensitize these immune effector cells to
`tumor antigen and produce a cytolytic response directed at the
`sites of tumor with minimal systemic toxicity. The application
`of immunotherapy is limited to immunogenic malignancies,
`those tumors which are known to be vulnerable to immune(cid:173)
`mediated cytotoxicity. Renal cell carcinoma and bladder cancer
`are both immunogenic, and therefore should be responsive to
`immunotherapy. Preliminary in vitro data suggest that prostate
`cancer cells can also respond to immunomodulation by cyto(cid:173)
`kines. 2·3·4 Modern immunotherapy can be applied to neoplastic
`disease in one of several manners: ( 1) by systemic or locoregio(cid:173)
`nal infusion of immunostimulatory agents; (2) by passively
`transferring immune cells with antitumor reactivity (such as
`LAK or TIL cells) to the tumor-bearing host to attack sites of
`cancerous cells (adoptive immunotherapy); or (3) by vaccina(cid:173)
`tion with tumor cells transformed with genes or other immune
`stimulators to promote the generation of immune lymphoid cells
`with anti-tumor activity, or systemic or locoregional transfec(cid:173)
`tion of tumor cells with genetic material that can either induce
`tumor cell differentiation, cause direct cytolytic activity, pro(cid:173)
`duce regional cytokine secretion, or enhance MHC receptor
`expression ("gene therapy"). This latter method is referred to
`as active immunotherapy and intensive investigation is currently
`underway.
`
`Adoptive Immunotherapy
`
`Adoptive immunotherapy involves the in vitro growth, ex(cid:173)
`pansion, and immune-modification of lymphoid cells (NK and
`T cells) prior to reinfusion back into the host.5•6•7 One such
`example is TIL therapy, which has been shown to cause regres(cid:173)
`sion of bulky tumors in a variety of animal tumor models and
`in humans. TILs are lymphoid cells isolated from fresh solid
`tumors upon co-culturing a tumor-cell suspension with the cyto(cid:173)
`kine interleukin-2. After expansion of these cells in culture,
`which usually takes 3 to 4 weeks, TILs are reinfused into the
`
`patient in the hope that. these cytotoxic T lymphocytes will
`recognize, home to, and ~estroy tumor deposits throughout the
`body.6
`8 Our own data at UCLA using TILs in patients with
`•
`advanced renal cell carcinoma resulted in a response rate of
`34% (see below).
`
`Active Immunotherapy
`
`Active or specific immunotherapy refers to the immunization
`of a patient with agents that will increase the host immunologic
`response against the tumor. The first report dates to 1971 when
`a patient with metastatic renal cell carcinoma was cured .after
`receiving serum obtained from a relative, also with renal cell
`carcinoma, but in remission. 9 Current research is concentrated
`on creating tumor vaccines. During the intervening 20 years,
`the study of imrnunotherapy has introduced systemic cytokine
`treatment modalities as well as the adoptive immunotherapeutic
`techniques of LAK cells and TILs into the war against cancer.
`Tumor vaccine protocols utili~ the ability of cytokines to
`increase tumor cell immunogenicity, thereby increasing the
`ability of the host immune system to recognize and destroy
`cancer foci. Autologous tumor cells are transfected in vitro with
`cytokine producing genes. These transfected cells, now produc(cid:173)
`ing cytokines and expressing increased MHC class I antigens,
`are r~transplanted into th.e host where they stimulate a tumor(cid:173)
`specific immune resp~mse. Cytokine production occurs only at
`the implant site, thereby producing a strong antitumor response
`without systemic toxicity. The stimulated immune effector
`agents can then diffuse throughout the host to hunt down and
`destroy other tumor foci and provide immunological memory
`to the host. Studies in animals with subcutaneously placed vac(cid:173)
`cines have demonstrated potent, specific, and long-lasting anti(cid:173)
`tumor immunity with protection upon rechallenge with
`tumor. 10
`11
`•
`Another approach to modulating the host immune response
`is by increasing the tumor's immunogenicity in vivo by sys(cid:173)
`temic or intralesional injections of genetic elements that will
`transfect tumor cells and either enhance MHC class I expres(cid:173)
`sion, stimulate regional cytokine production, or introduce for(cid:173)
`eign antigenic material. 12 Such genetic material includes cyto(cid:173)
`kine, suicide, and suppressor genes. This modality of gene
`therapy is currently under investigation, and is so far limited by
`technical difficulties involving efficient and safe gene delivery
`systems.
`
`Cytokines
`
`Cytokines are important elements in the antitumor response:
`they are soluble factors that are responsible for communication
`between cells of the immune system. In addition to direct tu(cid:173)
`moricidal effects, they also activate effector components of the
`immune system. t.i 3-i 9 The introduction of cytokine genes into
`tumor cells has been repeatedly proven to enhance antitumor
`immune responses in both in vitro and in vivo studies. The
`following are the cytokines which have shown the most promise
`in genitourinary neoplasms. Tumor necrosis factor-a (TNF-a)
`has direct effects on neoplastic cells resulting in cell death.
`Interferon.;.a (IFN-a) induces a marked increase in the surface
`expression of class I MHC antigens in addition to direct antitu-
`
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`i ··f
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`SYSTEMIC IMMUNOTHERAPY GENITOURINARY NEOPLASMS
`
`/ 8 71
`
`mor activity. It also up-regulates adhesion molecule expression
`on the surface of tumor cells, aiding the immune response. Inter(cid:173)
`feron-y (IFN-y) induces a marked increase in the surface
`expression of class I and II MHC antigens. Interleukin-2 (IL-
`2) is produced by activated T cells and causes proliferation of
`cytotoxic T (Tc). natural killer (NK), and LAK cells capable
`of lysing autologous, syngeneic, or allogeneic tumor cells, but
`not nonnal cells. IL-2 has no direct antitumor effect, but secre(cid:173)
`tion of IL-2 from tumor cells abrogates tumorigenicity by stimu(cid:173)
`lating the activation and proliferation of immune effector
`cells.20
`
`IMMUNOTHERAPY FOR METASTATIC RENAL
`CELL CARCINOMA
`
`·
`
`In 1996, 30,600 Americans will be diagnosed with renal cell
`carcinoma, accounting for 2 percent of all adult malignancies.21
`Surgically unresectable disease has a poor outcome, as no sue-
`cessful radio- or chemotherapy strategies have been devised. 22
`The natural history of renal cell carcinoma is not always predict(cid:173)
`able, and spontaneous regression of metastases after nephrec(cid:173)
`tomy does occur, albeit rarely (less than 1 %). Early observations
`of spontaneous regression, along with the discovery of circulat(cid:173)
`ing humoral and cellular elements in such patients, delayed
`growth of metastatic lesions, and varying tumor doubling times,
`suggested involvement of the immune system in the natural
`host response to this neoplasm.23 Since then, renal cell carci(cid:173)
`noma has become a paradigm for the immunotherapeutic ap(cid:173)
`proach to treating solid organ malignancies.
`Initial approaches to immunotherapy utilized nonspecific im(cid:173)
`mune stimulators, such as bacillus Calmette-Guerin, or xenoge(cid:173)
`neic RNA-treated lymphocytes (probably a stimulator of inter-
`.
`) D
`·
`· · · I
`24-26 th·
`th
`·
`ach
`is appro
`feron production . esp1te 1mtia en us1asm,
`ultimately yielded no significant improvement in pr9gnosis.27
`Several studies with BCG showed some initial benefit although
`30 A similar
`larger randomized studies were not performed.28
`-
`situation holds for Corynebacterium parvum31 and transfer fac(cid:173)
`tor, 32 two other nonspecific agents no longer in vogue. One
`third of the patients enrglled in a pilot study to assess the antitu"
`mor activity of l,2"benzopyrene responsed to treatment, yet
`subsequent phase II studies with this nonspecific agent w.ere
`associated with only a 6% response rate. These nonspecific
`agents are now mainly of historical interest with regards to
`treating renal cell carcinoma.
`
`.Biologic Therapy with Cytokines
`
`The isolation, identification, ~d molecular cloning of IL-2
`revolutionized the field of cancer immtinotherapy and signifi-
`.
`al
`11
`.
`33.34
`cantly altered the treatmentofmetastlc ren ce carcmoma.
`Since then, other immunostimulatory cytokines have been iden(cid:173)
`tified and purified. With the advent of recombinant DNA tech(cid:173)
`nology, the ability to produce large quantities of these cytokines
`has resulted in their wide-spread use and, in a relatively short
`period of time, these agents have become a? ac.cepte~ tre.atment
`for metastatic disease. To date, most studies mvestigatmg the
`use of cytokines in. the treatment of metastatic renal cell c~ci­
`noma have used IFN-a, IL-2, combinations of these cytokmes,
`or adoptive immunotherapy with TILs or LAK cells .. The role
`
`of a new generation of cytokines such as IL-4, IL-7, IL-12, and
`GM"CSF is currently under investigation.
`
`Interferon Alpha and Gamma
`
`Research at UCLA in the early 1980s was the among the
`first to demonstrate the effectiveness of IFN-a in the treatment
`of metastatic renal cell carcinoma.35 Independent studies at the
`same time confirmed the regression of metastatic disease with
`objective response rates of 16% to 26% lasting an average of
`37 These numbers have not changed signifi(cid:173)
`8 to 1 O months. 36
`•
`cantly in the past decade, despite numerous phase II trials and
`attempts at modifying doses and dosing schedules. 38-49 Table
`84-1 summarizes the major studies of the past decade, demon(cid:173)
`strating a reproducible response rate of 15-20 percent and a
`response duration of 8 to I 0 months. Responses appear indepen(cid:173)
`dent of the preparation and dosing used. Improved response
`rates of 30% and durable clinical responses lasting more than
`27 months can be seen in a select subset of patients treated with
`IFN-a.45.47 These patients have had a prior nephrectomy, no
`previous chemotherapy or radiation therapy, good to excellent
`performance status, and primarily pulmonary metastases. (Lung
`metastases appear more responsive to IFN-a therapy than those
`of other viscera.43 At UCLA, survival rates increased from 49
`to 115 weeks in IFN-a treated patients with these favorable
`prognostic variables.47
`Side effects of IBN-a treatment include fever, chills, myal(cid:173)
`gia, anorexia, and headache. These are usually associated with
`the initial dosing and often improve spontaneously with contin(cid:173)
`ued administration of the drug. Reversible hematologic and he(cid:173)
`patic changes are occasionally noted, but they, too, usually re(cid:173)
`51
`solve without necessitating changes in dosing.50
`•
`Combining accessory agents with IFN-a has been investi(cid:173)
`gated as a means of increasing responsiveness and decreasing
`
`TABLE 84-1. Phase II trials of interferon-alpha for the
`treatment of metastatic renal cell cancer
`
`Investigators
`DeKernion et al, 198335
`Quesada et al, 198336
`Neidart.et al, 198441
`Figlin et al, 198548
`Quesada et al, 198537
`Kirkwood et al, 198538
`Umeda and Niijima, 198640
`Fossa et al, 198657
`Muss et al, 198745
`Creagan et al, 198749
`Sarna et al, 198747
`
`Figlin et al, 198939
`Minasian et al, 199344
`Total
`·
`
`Patients
`
`Response
`
`43
`19
`33
`23
`50
`30
`226
`18
`97
`29
`43
`22
`1'8
`159
`651
`
`16.5%
`26%
`15%
`133•
`26%
`23%
`17.7%
`333•
`7%t
`34%;
`14%§
`14%*
`26%
`10%*
`20%
`
`.
`* Addition of vinblastine (0.15 mgikg).
`t Select subpopulation ( + prior nephrectomy, - prior
`chemotherapy, - borie mets) had 23% response rate.
`.
`:j: Aspirin, 600 mg PO qid.
`§Select subpopulation ( + prior nephrectomy, - prror
`chemotherapy, - bone mets) had 24% response rate.
`
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`I CHAPTER 84
`
`TABLE 84-2. Phase II trials of interferon-beta and gamma
`for the treatment renal cell cancer
`
`Investigators
`Rinehart et al, 198662
`Rinehart et al, 198664
`Quesada et al, 198763
`Aulitzky et al, 198965
`Ellerhorst et al, 199461
`Total
`
`* Interferon-beta
`
`Patients
`
`Response
`
`18
`13
`33
`·22
`35
`121
`
`17%*
`0%
`7%
`27%
`15%
`14%
`
`toxicity. In one study, the addition of aspirin increased response
`rates to 34%, but few changes in constitutional symptoms (the
`reason for adding aspirin to the treatment protocol) occurred.49
`In vitro, the administration of 5-FU increases the susceptibility
`of renal cell carcinoma to LAK cells, and the combined adminis(cid:173)
`tration of 5-FU and IFN for the treatment of bladder cancer
`54 Several studies have investigated
`has also shown promise. 52
`-
`using different combinations of IFN-a and chemotherapeutic
`agents to treat renal ceH carcinoma, and have demonstrated a
`favorable response rate. At the M. D. Anderson Cancer Center,
`Houston, Texas, combinations of IFN-a, mitomycin C, and 5-
`FU were found to be synergistic and improved the response
`rate to 35%.55 With the combination ofIL-2, IFN-a, and 5-FU,
`the response rate increased to 45 percent with only moderate
`toxicity.56 The addition of other agents, such as vmblastine,48,57
`doxorubicin,58 and BCNU59 do not appear to alter the response
`rate or the duration of the response, yet results in increased
`fatigue, hepatotoxicity, and myelosuppression.60
`Several studies investigating the use of IFN-yin the treatment
`of metastatic renal cell carcinoma are summarized in Table 84-
`2. The response rates and duration of response were favorable,
`but no better than those of IFN-a or IL-2.61 - 65 The toxicities
`are similar, and consist primarily of malaise, fever, anorexia,
`and headache. As discussed earlier, IFN-a upregulates expres(cid:173)
`sion of MHC class I antigens while IFN-y increases both class
`I and II expression. Because these two cytokines have different
`roles in stimulating the immune response, there is speculation
`that a treatment approach combining both IFN-a and IFN-y
`would be complementary, and thus more effective. In vitro stud(cid:173)
`ies do demonstrate synergistic activity between IFN-a and IFN(cid:173)
`y, although with a significantly added toxity.66 Preliminary clin(cid:173)
`ical trials have failed to show any additive effects, and toxicity
`was significant. 67- 69
`
`IL-2 alone or co-administered with LAK cells. The overall re(cid:173)
`sponse rate was 18% (IrJ..2 alone) and 35% (IL-2 and LAK
`cells). Other researchers have confirmed these resu]ts72
`73 and,
`•
`when combined with further studies comprising a total of 255
`patients treated with IL-2, an overall objective response rate of
`15% and a duration of almost 2 years was demonstrated.74 This
`data was used by the United States Food and Drug Adminstra(cid:173)
`tion in 1992 when IL-2 was approved for the treatment of meta(cid:173)
`static renal cell carcinoma. Rosenberg has summarized his ex(cid:173)
`perienced with high dose IL-2 therapy and metastatic renal cell
`carcinoma, noting a 20% overall response rate.75 Table 84-3
`summarizes the major clinical investigations of IL-2 on meta(cid:173)
`static renal cell carcinoma. These studies have identified certain
`patient characteristics associated with a better response to IL-
`2 therapy: good to .excellent performance scores and either lung,
`lymph node, or small-volume extrahepatic abdominal disease.
`The use of IL-2 is associated with significant side effects,
`the most serious of which is a prerenal azotemia with resultant
`hypotension, pulmonary edema, renal failure, and fluid reten(cid:173)
`tion. Myocardial infarction, gastrointestinal bleeding and perfo(cid:173)
`ration, and death may also occur. (Although the mortality from
`IL-2 .therapy was initially set at 1.5% to 4%,90
`91 more recent
`•
`data show reduced toxicity as more experience is gained with
`this treatment modality.75 At UCLA we have not experienced
`any deaths in our series.) These major toxicities are dose-related
`and result from increased membrane permeability and subse(cid:173)
`quent fluid and colloid loss into viscera and soft tissue. 76-80
`Other common side effects include fever, chi11s, anorexia, gas(cid:173)
`trointestinal upset, mental status changes, tachyarrythmias, and
`third spacing of fluids. These are reversible and usually resolve
`within 72 hours of discontinuing therapy.
`To prevent these severe but largely reversible toxicities, alter(cid:173)
`native infusion schedules and dosing regimens have been de(cid:173)
`vised. Several studies have compared continuous versus bolus
`81
`83 Results demonstrate similar re(cid:173)
`IL-2 administration.72•
`-
`sponse rates of 15% to 20% and equivalent side effects between
`the two groups, although continuous infusion of IL-2 requires
`less total drug.
`Other researchers have focused on ]ow-dose IL-2 therapy,
`especially since many metastic renal cell carcinoma patients
`are not candidates for high-dose treatment given their age, con(cid:173)
`comitant disease states, and overall incapacity. The results are
`inconsistent: although all studies associated the lower dose with
`decreased toxicity, some demonstrated similar efficacy between
`high- and ]ow-dose IL-2 therapy,84•85 while others86 failed to
`
`I nterleukin-2
`
`TABLE 84·3. Phase II trials of interleukin-2 for the
`treatment of metastatic renal cell cancer
`
`IL-2 was the first cytokine demonstrated to mediate anti(cid:173)
`tumor effects via the host immune system. Unlike TNF, IL-2
`has no demonstrable direct and antitumor effect, but activates
`immune effector cells which then target neoplastic lesions. 20 In
`vitro and in vivo studies de~onstrate that IL-2 can generate
`LAK cells, enhance NH cell function, augment alloantigen re(cid:173)
`sponsiveness, stimulate growth Tc celJs, and mediate the regres(cid:173)
`~mn of large tumor burdens.70 The first large studies investigat(cid:173)
`mg the therapeutic role of IL-2 in metastatic renal cell
`carcinoma were undertaken at the National Cancer Institute
`(NCI).71 One hundred and thirty-two patients were treated with
`
`lnve~tigators
`West et al, 198772
`Fisher et al, 198873
`Rosenberg et al, 198991
`Bukowski et al, 199081
`Geertsen et al, 199282
`Weiss et al, 199283
`Rosenberg et al, 199271
`Atkins et al, 1993218
`Rosenberg et al, 199475
`Total
`
`Patients
`
`Response
`
`40
`35
`54
`41
`30
`94
`60
`71
`143
`568
`
`32%
`16%
`22%
`12%
`20%
`18%
`18%
`17%
`20%
`20%
`
`Breckenridge Exhibit 1100
`Sokoloff
`Page 006
`
`

`

`.I
`
`SYSTEMIC lMMlJNOTHERAPY GENITOURINARY NEOPLASMS
`
`I 873
`
`TABLE 84-4. Phase II trials of combination cytokine
`therapy for metastatic renal cell cancer
`
`Investigators
`Rosenberg et al, 198989
`Mittleman et al, 1990219
`Kirchner et al, 1990220
`Atzpodien et al, 1990221
`Atzpodien et al, 199093
`Hirsch et al, 199094
`Bukowski et al, 1990222
`Thomas et al, 1992223
`Spencer et al, 1992224
`Budd et al, 1992225
`Figlin et al, 199292
`Sznol et al, 1992226
`Rosenberg, 199271
`!Ison et al, 1992227
`Lipton et al, 1993228
`Atkins et al, 1993218
`Bermann et al, 1993229
`Vogelzang et al, 199390
`Total
`•
`
`Patients
`35
`18
`17
`17
`14
`15
`20
`34
`22
`21
`52
`42
`41
`34
`39
`28
`30
`42
`521
`
`Response
`31 % ...
`22%
`29%
`36%
`35%
`40%
`15%
`6%
`5%
`10%
`25%
`19% ...
`34%
`12%
`33%
`11 %
`30%
`12%
`22%
`
`... Includes lymphocyte-activated killer cells.
`
`observe any objective response with low-dose treatment. Fur(cid:173)
`ther studies using low-dose IL-2 either via continuous infusion
`or subcutaneous administration are currently underway.
`
`Combination Therapy: IL-2 and IFN-a
`
`Combining IL-2 infusion with other cytokines has also been
`investigated as a means of reducing toxicity. After in vitro stud(cid:173)
`f IL 2
`.
`d
`. .
`. '
`'th IFN
`87 88
`-a, ·
`1es demonstrate a synerg1st1c act1v1ty o
`- w1
`the first human trials were undertaken at the NCI. Patients with
`metastatic renal cell carcinoma had a 31 % response rate to this
`treatment. 89 Since then, other studies have investigated this
`combined approach, with an emphasis on outpatient, low-dose
`regimens. The results are listed in Table 84-4. These studies
`show a wide range of response rates with an average of 22%,
`depending on patient selection and study assessment param(cid:173)
`eters. Since 1988, 52 patients at UCLA have been treated with
`combination IL-2 and IFN-a, with results comparing favorably
`to those achieved with high-dose IL-2 alone: the response rate
`was 25%, the median duration of response was 23 months,
`and the median duration of survival was 34 months or more.92
`
`Similar studies have confirmed these findings. 93•94 These phase
`II protocols demonstrate that combination IL-2/IFN-a can be
`administered to patients with metastatic renal cell carcinoma
`successfully and safely on an outpatient basis with results simi(cid:173)
`lar to that of high-dose IL-2 alone. ·Tue main adverse effects
`of combination therapy-fever, chills, nausea, anorexia, and
`hypotension-are less severe than those of high-dose IL-2 alone
`and are easily treated on a symptomatic basis.
`
`Adoptive Immunotherapy for Metastatic Renal Cell
`Carcinoma
`
`Autolymphocyte Therapy
`
`The theoretical basis of autolymp~ocyte therapy (ALT) relies
`on activation of memory T-lymphocytes (mT cells) in patients
`
`with metastatic cancer. These are T cells that have been exposed
`in vivo to tumor antigens and have the potential for mediating
`tumor regression following nonspecific activation.95 Activation
`is performed by incubating mT cells (from peripheral blood)
`with anti-T cell receptor (CD-3) antibodies, thus triggering a
`clonal proliferation of effector cells.96•97 In 1990, Osband and
`colleagues reported a 21 % response rate in 90 patients with
`metastatic renal cell carcinoma, achieving a significant survival
`advantage (21 months versus 8.5 months) with only mild toxic(cid:173)
`ity.98 Further studies are currently in progress,99•100 but random(cid:173)
`ized trials comparing ALT to IL-2 have not been performed. 101
`
`Lymphokine-Activated Killer Cellular Therap'
`
`Lymphokine-activated killer (LAK) cells are generated by
`cultivating peripheral blood cells with IL-2 for 3 to 4 days
`and represent the nonspecific arm of immune effector cells that
`mediate tumorilysis in a non-MHC restricted fashion. 102 After
`104 demonstrated that IL-2 plus LAK therapy
`initial studies 103
`•
`resulted in the regression of established animal tumor models
`for melanoma, renal cell, sarcoma, colon adenocarcfooma, and
`bladder carcinoma, clinical studies were begun.71 LAK cells
`are infused into the patient along with IL-2 in either high or
`low doses. Side effects are related to the dose of IL-2 adminis(cid:173)
`tered and responsiveness is related to patient performance pro(cid:173)
`fil