V O L U M E
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`2 4
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`䡠 N U M B E R 1 3
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`䡠 M A Y 1
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`2 0 0 6
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`JOURNAL OF CLINICAL ONCOLOGY
`
`C O R R E S P O N D E N C E
`
`Treatment of Metastatic Renal
`Cell Carcinoma With Autologous
`T-Lymphocytes Genetically Retargeted
`Against Carbonic Anhydrase IX: First
`Clinical Experience
`
`TO THE EDITOR: Adoptive transfer of autologous T-lymphocytes
`that are gene transduced to express antigen-specific receptors repre-
`sents an experimental therapy to provide tumor-specific immunity to
`cancer patients. We studied safety and the proof of this concept in
`patients with metastatic renal cell carcinoma (RCC), and have en-
`countered toxicity that is likely to be antigen specific.
`We have constructed a single-chain antibody-type (scFv) –re-
`ceptor based on murine monoclonal antibody (mAb) G250.1 This
`mAb recognizes an epitope on carboxy-anhydrase-IX (CAIX),
`which is frequently overexpressed on clear cell RCC. Following
`retroviral introduction of the scFv(G250) transgene into primary
`human T-cells, the scFv(G250) receptor is expressed on the surface
`of these cells, which enables them to recognize CAIX and to exert
`antigen-specific effector functions, such as cytokine production
`after exposure to CAIX and the killing of CAIX⫹ RCC cell lines.2,3
`We treated patients with scFv(G250)-transduced T-cells in an
`inpatient dose-escalation scheme of intravenous (IV) doses of 2 ⫻
`107 cells at day 1; 2 ⫻ 108 cells at day 2; 2 ⫻ 109 cells at days 3
`through 5 (treatment cycle 1); and 2 ⫻ 109 cells at days 17 to 19
`(treatment cycle 2), in combination with human recombinant
`interleukin-2 (IL-2; Chiron Corporation, Amsterdam, the Nether-
`lands), subcutaneously, 5 ⫻ 105 U/m2 twice daily administered at
`days 1 to 10 and days 17 to 26. This protocol was approved by the
`governmental regulatory authorities and the institutional medical
`ethical review board. Adaptations to this protocol were imple-
`mented only after approval by these boards. Written informed
`consent was obtained from all patients.
`In this letter, we report on the clinical experiences of the first three
`patients. The patients had CAIX⫹ metastatic clear cell RCC, had
`undergone tumor nephrectomy, and had progressive disease after 6 to
`17 months of interferon alfa (IFN-␣) treatment. From all, we success-
`fully generated functional scFv(G250)⫹ T-cells ex vivo (Table 1).
`Infusions of these gene-modified T-cells were initially well-tolerated.
`However, after four to five infusions, liver enzyme disturbances reach-
`ing National Cancer Institute Common Toxicity Criteria grades 2 to 4
`developed. These toxicities necessitated the cessation of treatment in
`patient 1 and patient 3, corticosteroid treatment in patient 1, and
`reduction of the maximal T-cell dose to 2 ⫻ 108 T-cells in patient 2 and
`patient 3. After treatment, patients showed progressive disease be-
`tween 36 and 106 days. In order to elucidate the underlying mecha-
`nisms accounting for the liver toxicity, a liver biopsy was performed on
`patient 1, showing a discrete cholangitis with T-cell infiltration around
`the bile ducts, and CAIX expression on the bile duct epithelial cells.
`Although technical limitations prohibited direct identification of
`
`scFv(G250)⫹ T-cells in these sections, these findings strongly suggest
`that the liver toxicity is caused by a specific attack of the scFv(G250)⫹
`T-cells against the CAIX⫹ bile duct epithelial cells.
`We transiently detected both scFv(G250)⫹ T-cells and
`scFv(G250) DNA copies in the circulation of all three patients from
`day 3 of treatment onward, using flow cytometry and quantitative
`real-time polymerase chain reaction (PCR). The time period during
`which the transduced cells were detected in the circulation depended
`on the method used, that is, up to 32 days by flow cytometry and up to
`53 days by PCR4 (Table 1).
`Before treatment, peripheral blood mononuclear cells did not
`show scFv(G250)-mediated functions, that is, specific cytolysis of
`CAIX⫹ target cells and production of IFN-␥on stimulation with such
`cells. After infusions of scFv(G250)-transduced T cells, these activities
`became detectable in all three patients (Table 1).
`All three patients developed low levels of anti-scFv(G250) anti-
`bodies between 37 and 100 days after the start of T-cell therapy, which
`were directed against the G250 idiotype (id). Remarkably, these re-
`sponses were less frequent in RCC patients treated with weekly IV
`infusions of 50 mg chimeric G250 mAb (ie, in 6% to 30% of pa-
`tients),5,6 indicating that the expression of scFv(G250) on the cell
`membrane of T-cells elicits a relatively efficient immune response
`against the murine G250-id. Such response may hamper the effective
`clinical use of murine-human chimeric receptors, and may require
`construction of receptors from completely human mAbs.
`In summary, our data show clear in vivo reactivity of autologous
`T-cells that have been genetically retargeted using a single-chain
`antibody-type receptor. The observed liver toxicity is most likely due
`to the reactivity of transduced T-cells against the target antigen ex-
`pressed on normal tissue, that is, the epithelial cells lining the bile
`ducts, and thereby hinders administration of T-cells in numbers that
`can be expected to yield antitumor activity. We consider our observa-
`tions, together with those from T-cell therapies directed against self-
`antigens,7,8 relevant for other studies involving T-cell retargeting for
`therapeutic purposes. Ideally, the target antigens for such studies
`should be carefully chosen, so as to be expressed only by malignant
`cells and not by normal cells.
`Alternatively, strategies need to be developed to attenuate activity
`of retargeted T-cells against normal tissues expressing target antigen to
`circumvent the observed adverse events.
`In order to prevent liver toxicity in future patients, we have
`modified our clinical protocol into a conventional phase I study, and
`have included an infusion of 5 mg cG250 antibody 3 days before the
`first infusion of gene-modified T-cells. The rationale of this amended
`protocol is that repeated administration of cG250 has not only been
`shown to be clinically safe and well-tolerated by more than 200 pa-
`tients,9 but more importantly, cG250 localizes to RCC metastasis but
`not to the liver, after having saturated uptake by liver tissue (but not
`RCC metastasis) by a single low dose of cG250.6,10,11 By pretreating
`patients with a single, low dose of cG250, we aim to protect the bile
`duct epithelium from the damaging effects exerted by scFv(G250)⫹
`
`e20
`
`Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp e20-e22
`
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`
`Copyright © 2022 American Society of Clinical Oncology. All rights reserved.
`
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`

`Correspondence
`
`Table 1. Characteristics of Preinfusion scFv(G250)-Transduced T-Cells and of Peripheral Blood Following Immunogene Therapy
`
`Parameter
`
`Patient 1
`
`Patient 2ⴱ
`
`Patient 3ⴱ
`
`Preinfusion characteristics of scFv(G250)-transduced T-cells
`Cell and DNA copy counts
`No. of infusions
`Total No. of T-cells (⫻ 109)
`Mean % scFv(G250)⫹ T-cells
`Total No. of scFv(G250)⫹ T-cells (⫻ 109)
`Mean No. of scFv(G250) DNA copies per scFv(G250)⫹ T-cell
`scFv(G250)-mediated functions
`CAIX-specific cytolysis (LU20)§
`LU20/106 scFv(G250)⫹ T-cells
`Total LU20
`CAIX-specific IFN-␥ production, ng per 106 scFv(G250)⫹ T-cells per 24h
`Characteristics of peripheral blood samples during immunogene therapy
`Circulating scFv(G250)⫹ T-lymphocytes
`Peak, day
`Peak level, cells/␮l
`Period during which cells detectable㛳
`Circulating scFv(G250) DNA copies
`Peak, day
`Peak level, cells/␮l
`Period during which DNA detectable
`Human anti-scFv(G250) antibodies
`Day of first appearance
`Peak, day
`Peak level, ng/ml
`ScFv(G250)-mediated functions in vitro
`CAIX-specific cytolysis
`Peak, day
`Peak level, LU20/106 PBMC
`CAIX-specific IFN-␥ production
`Peak, day
`Peak level, ng/ml per 106 PBMC per 24h
`
`4†
`3.99
`53
`2.13
`2.3
`
`372
`792, 204
`33
`
`7
`5.3
`3-23
`
`tfd
`tfd
`tfd
`
`37
`57¶
`706
`
`8
`16
`
`8
`9
`
`5/3‡
`0.8/0.59
`52/76
`0.43/0.42
`4.5/6.8
`
`104/82
`78, 774
`33/24
`
`10/21
`2.7/1.6
`3-32
`
`17/19
`7.1/5.2
`tfd-53
`
`100
`100¶
`190
`
`8/22
`29/44
`
`8/22
`25/32
`
`4†
`0.60
`63
`0.38
`2.8
`
`88
`33, 274
`28
`
`6
`0.8
`3-7
`
`8
`5.3
`3-32
`
`79
`79
`292
`
`5
`26
`
`5
`37
`
`Abbreviations: scFv, single-chain antibody type; LU, lytic unit; CAIX, carboxy-anhydrase IX; IFN, interferon; h, hour; PBMC, peripheral blood mononuclear cells; tfd,
`too few data points to allow data assessment.
`ⴱT-cell dose reduced to a maximum of 2 ⫻ 108 T-cells.
`†Treatment cycle 1 only.
`‡Treatment cycle 1/treatment cycle 2.
`§One LU20 is defined as the number of effector T-cells required to lyse 20% of 2,500 CAIX target cells in a 4 h 51Cr release assay.
`㛳Day(s) after start of treatment (day 1 ⫽ day of first infusion).
`¶Last day of observation.
`
`T-cells. The Dutch regulatory authorities have approved this amended
`protocol and accrual of patients is currently ongoing.
`
`Cor H.J. Lamers, Stefan Sleijfer, Arnold G. Vulto,
`Wim H.J. Kruit, Mike Kliffen, Reno Debets,
`Jan W. Gratama, and Gerrit Stoter
`Departments of Medical Oncology, Pharmacy, and Pathology, Erasmus
`University Medical Center–Daniel den Hoed Cancer Center, Rotterdam,
`the Netherlands
`
`Egbert Oosterwijk
`Department of Experimental Urology, University Medical Center, Nijmegen,
`the Netherlands
`
`REFERENCES
`1. Weijtens MEM, Willemsen RA, Valerio D, et al: Single chain Ig/gamma
`gene-redirected human T lymphocytes produce cytokines, specifically lyse tumor
`cells, and recycle lytic capacity. J Immunol 157:836-843, 1996
`2. Lamers CH, Willemsen RA, Luider BA, et al: Protocol for gene transduction
`and expansion of human T lymphocytes for clinical
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`cancer. Cancer Gene Ther 9:613-623, 2002
`
`3. Lamers CHJ, Willemsen RA, van Elzakker P, et al: Phoenix-ampho outper-
`forms PG13 as retroviral packaging cells to transduce human T cells with
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`Gene Ther 16:1452-1462, 2005
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`fractionated radioimmunotherapy using 131I-labeled chimeric G250 in metastatic
`renal cancer. J Nucl Med 45:1412-1421, 2004
`6. Brouwers AH, Mulders PF, de Mulder PH, et al: Lack of efficacy of two
`consecutive treatments of radioimmunotherapy with 131I-cG250 in patients with
`metastasized clear cell renal cell carcinoma. J Clin Oncol 23:6540-6548, 2005
`7. Rosenberg SA, Dudley ME: Cancer regression in patients with metastatic
`melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl
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`www.jco.org
`
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`

`Correspondence
`
`9. Bleumer I, Knuth A, Oosterwijk E, et al: A phase II trial of chimeric
`monoclonal antibody G250 for advanced renal cell carcinoma patients. Br J
`Cancer 90:985-990, 2004
`10. Steffens MG, Boerman OC, Oyen WJ, et al: Intratumoral distribution of
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`carcinoma: Implications for fractionated dose radioimmunotherapy. Cancer Res
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`monoclonal antibody G250. Anticancer Res 19:1197-1200, 1999
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`DOI: 10.1200/JCO.2006.05.9964
`■ ■ ■
`
`Acknowledgment
`This letter was supported by the Dutch Cancer Foundation
`(Grant No. DDHK99-1865), European Commission Grant No.
`
`QLK3-1999-01262, and the Cancer Research Institute, New York, NY
`(clinical investigation grant “Immunogene therapy of metastatic renal
`cell cancer patients”). This letter was presented in part at the European
`Society of Gene Therapy 2004 meeting in Tampere, Finland and at the
`International Society for Cellular Therapy 2005 meeting in Vancou-
`ver, British Columbia, Canada.
`
`Authors’ Disclosures of Potential Conflicts of Interest
`The authors indicated no potential conflicts of interest.
`
`e22
`
`JOURNAL OF CLINICAL ONCOLOGY
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`JOURNAL OF CLINICAL ONCOLOGY
`
`O f f i c i a l
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`J o u r n a l
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`o f
`
`t h e A m e r i c a n
`
`S o c i e t y
`
`o f C l i n i c a l O n c o l o g y
`
`Vol 24, No 13
`
`C O N T E N T S
`
`May 1, 2006
`
`Presidential Address
`ASCO in the 21st Century: Challenges and Opportunities—ASCO Presidential Address 2005
`David H. Johnson .......................................................................................................................................................................................................................... 1967
`
`Editorials
`Inherited Genetic Markers and Cancer Outcomes: Personalized Medicine in the
`Postgenome Era
`Timothy R. Rebbeck (see article on page 1982) ..................................................................................................................................................... 1972
`Exploring Dose-Intensity: Carefully Comparing High-Dose With Low-Dose
`External-Beam Radiotherapy for Prostate Cancer
`Howard M. Sandler (see article on page 1990) ...................................................................................................................................................... 1975
`Sentinel Lymph Node Histopathology in Breast Cancer: Minimal Disease
`Versus Artifact
`Beverley A. Carter and David L. Page (see article on page 2013) ............................................................................................................ 1978
`Reponses to Topoisomerase-I Inhibitors in Extensive Small-Cell Lung Cancer:
`Chance or Chromosomes?
`Michael C. Perry (see articles on pages 2038 and 2044) ................................................................................................................................. 1980
`
`Original Reports
`
`GENITOURINARY CANCER
`Impact of IGF-I and CYP19 Gene Polymorphisms on the Survival of Patients With
`Metastatic Prostate Cancer
`Norihiko Tsuchiya, Lizhong Wang, Hiroyoshi Suzuki, Takehiko Segawa, Hisami Fukuda, Shintaro Narita,
`Masaki Shimbo, Toshiyuki Kamoto, Kenji Mitsumori, Tomohiko Ichikawa, Osamu Ogawa, Akira Nakamura,
`and Tomonori Habuchi (see editorial on page 1972) ......................................................................................................................................... 1982
`Dose-Response in Radiotherapy for Localized Prostate Cancer: Results of the Dutch
`Multicenter Randomized Phase III Trial Comparing 68 Gy of Radiotherapy With 78 Gy
`Stephanie T.H. Peeters, Wilma D. Heemsbergen, Peter C.M. Koper, Wim L.J. van Putten, Annerie Slot,
`Michel F.H. Dielwart, Johannes M.G. Bonfrer, Luca Incrocci, and Joos V. Lebesque (see editorial on page 1975) ............ 1990
`Impact of Immune Parameters on Long-Term Survival in Metastatic Renal Cell Carcinoma
`Frede Donskov and Hans von der Maase ................................................................................................................................................................... 1997
`
`(continued on following page)
`
`Journal of Clinical Oncology (ISSN 0732-183X) is published 36 times a year, three times monthly, by American Society of Clinical Oncology, 1900 Duke St, Suite 200, Alexandria,
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`Mortality After Major Surgery for Urologic Cancers in Specialized Urology Hospitals:
`Are They Any Better?
`Badrinath R. Konety, Veerasathpurush Allareddy, Sanjukta Modak, and Brian Smith .......................................................... 2006
`
`BREAST CANCER
`Axillary Sentinel Lymph Nodes Can Be Falsely Positive Due to Iatrogenic
`Displacement and Transport of Benign Epithelial Cells in Patients With
`Breast Carcinoma
`Ira J. Bleiweiss, Chandandeep S. Nagi, and Shabnam Jaffer (see editorial on page 1978) ................................................ 2013
`Sequential Preoperative or Postoperative Docetaxel Added to Preoperative
`Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: National Surgical
`Adjuvant Breast and Bowel Project Protocol B-27
`Harry D. Bear, Stewart Anderson, Roy E. Smith, Charles E. Geyer Jr, Eleftherios P. Mamounas,
`Bernard Fisher, Ann M. Brown, Andre Robidoux, Richard Margolese, Morton S. Kahlenberg,
`Soonmyung Paik, Atilla Soran, D. Lawrence Wickerham, and Norman Wolmark ..................................................................... 2019
`Prognosis After Ipsilateral Breast Tumor Recurrence and Locoregional Recurrences in
`Five National Surgical Adjuvant Breast and Bowel Project Node-Positive Adjuvant
`Breast Cancer Trials
`Irene L. Wapnir, Stewart J. Anderson, Eleftherios P. Mamounas, Charles E. Geyer Jr, Jong-Hyeon Jeong,
`Elizabeth Tan-Chiu, Bernard Fisher, and Norman Wolmark ........................................................................................................................ 2028
`
`LUNG CANCER
`Randomized Phase III Trial Comparing Irinotecan/Cisplatin With Etoposide/Cisplatin in
`Patients With Previously Untreated Extensive-Stage Disease Small-Cell Lung Cancer
`Nasser Hanna, Paul A. Bunn Jr, Corey Langer, Lawrence Einhorn, Troy Guthrie Jr, Thaddeus Beck,
`Rafat Ansari, Peter Ellis, Michael Byrne, Mark Morrison, Subramanian Hariharan, Benjamin Wang,
`and Alan Sandler (see editorial on page 1980) ....................................................................................................................................................... 2038
`Open-Label, Multicenter, Randomized, Phase III Study Comparing Oral
`Topotecan/Cisplatin Versus Etoposide/Cisplatin As Treatment for Chemotherapy-Naive
`Patients With Extensive-Disease Small-Cell Lung Cancer
`John R. Eckardt, Joachim von Pawel, Zsolt Papai, Antoaneta Tomova, Valentina Tzekova,
`Theresa E. Crofts, Sarah Brannon, Paul Wissel, and Graham Ross (see editorial on page 1980) ................................... 2044
`
`CLINICAL TRIALS
`Phase I, Pharmacokinetic, and Pharmacodynamic Study of Intravenously Administered
`Ad5CMV-p53, an Adenoviral Vector Containing the Wild-Type p53 Gene, in Patients With
`Advanced Cancer
`Anthony W. Tolcher, Desiree Hao, Johann de Bono, Alex Miller, Amita Patnaik, Lisa A. Hammond,
`Leslie Smetzer, Jill Van Wart Hood, James Merritt, Eric K. Rowinsky, Chris Takimoto, Dan Von Hoff,
`and S. Gail Eckhardt .................................................................................................................................................................................................................... 2052
`
`GASTROINTESTINAL CANCER
`Oral Uracil and Tegafur Plus Leucovorin Compared With Intravenous Fluorouracil and
`Leucovorin in Stage II and III Carcinoma of the Colon: Results From National Surgical
`Adjuvant Breast and Bowel Project Protocol C-06
`Barry C. Lembersky, H. Samuel Wieand, Nicholas J. Petrelli, Michael J. O’Connell, Linda H. Colangelo,
`Roy E. Smith, Thomas E. Seay, Jeffrey K. Giguere, M. Ernest Marshall, Andrew D. Jacobs,
`Lauren K. Colman, Atilla Soran, Greg Yothers, and Norman Wolmark .............................................................................................. 2059
`Chemotherapy Regimen Predicts Steatohepatitis and an Increase in 90-Day Mortality
`After Surgery for Hepatic Colorectal Metastases
`Jean-Nicolas Vauthey, Timothy M. Pawlik, Dario Ribero, Tsung-Teh Wu, Daria Zorzi, Paulo M. Hoff,
`Henry Q. Xiong, Cathy Eng, Gregory Y. Lauwers, Mari Mino-Kenudson, Mauro Risio, Andrea Muratore,
`Lorenzo Capussotti, Steven A. Curley, and Eddie K. Abdalla ..................................................................................................................... 2065
`
`(continued on following page)
`
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`PALLIATIVE CARE
`Patient-Controlled Methylphenidate for Cancer Fatigue: A Double-Blind, Randomized,
`Placebo-Controlled Trial
`Eduardo Bruera, Vicente Valero, Larry Driver, Loren Shen, Jie Willey, Tao Zhang, and J. Lynn Palmer ................ 2073
`
`NEUROONCOLOGY
`Response of Asymptomatic Brain Metastases From Small-Cell Lung Cancer to Systemic
`First-Line Chemotherapy
`Tatjana Seute, Pieter Leffers, Jan T. Wilmink, Guul P.M. ten Velde, and Albert Twijnstra ................................................. 2079
`Changes in Neurologic Function Tests May Predict Neurotoxicity Caused by Ixabepilone
`James J. Lee, Jennifer A. Low, Earllaine Croarkin, Rebecca Parks, Arlene W. Berman, Nitin Mannan,
`Seth M. Steinberg, and Sandra M. Swain .................................................................................................................................................................. 2084
`
`HEAD AND NECK CANCER
`Phase III Trial of an Emulsion Containing Trolamine for the Prevention of Radiation
`Dermatitis in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck:
`Results of Radiation Therapy Oncology Group Trial 99-13
`Elizabeth A. Elliott, James R. Wright, R. Suzanne Swann, Felix Nguyen-Taˆ n, Cristiane Takita, M. Kara Bucci,
`Adam S. Garden, Harold Kim, Eugen B. Hug, Janice Ryu, Michael Greenberg, Jerrold P. Saxton, Kian Ang,
`and Lawrence Berk ....................................................................................................................................................................................................................... 2092
`Prognostic Significance of [18F]-Misonidazole Positron Emission Tomography–Detected
`Tumor Hypoxia in Patients With Advanced Head and Neck Cancer Randomly Assigned to
`Chemoradiation With or Without Tirapazamine: A Substudy of Trans-Tasman Radiation
`Oncology Group Study 98.02
`Danny Rischin, Rodney J. Hicks, Richard Fisher, David Binns, June Corry, Sandro Porceddu,
`and Lester J. Peters ...................................................................................................................................................................................................................... 2098
`
`HEMATOLOGIC MALIGNANCIES
`Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential
`Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With
`Clinical Activity
`Sandra J. Strauss, Lenushka Maharaj, Susan Hoare, Peter W. Johnson, John A. Radford,
`Sarah Vinnecombe, Lynda Millard, Ama Rohatiner, Anthony Boral, Elizabeth Trehu, David Schenkein,
`Frances Balkwill, Simon P. Joel, and T. Andrew Lister .................................................................................................................................... 2105
`
`Review Article
`Prognosis and Management of Patients With Node-Negative Invasive Breast Carcinoma
`That Is 1 cm or Smaller in Size (stage 1; T1a,bN0M0): A Review of the Literature
`Emer O. Hanrahan, Vicente Valero, Ana M. Gonzalez-Angulo, and Gabriel N. Hortobagyi ................................................ 2113
`
`Art of Oncology
`The Attorney As the Newest Member of the Cancer Treatment Team
`Stewart B. Fleishman, Randye Retkin, Julie Brandfield, and Victoria Braun .................................................................................. 2123
`
`Correspondence
`A Call for Clinical Trials: Lipophilic Statins May Prove Effective in Treatment and
`Prevention of Particular Breast Cancer Subtypes
`Anjali S. Kumar, Michael Campbell, Christopher C. Benz, and Laura J. Esserman ................................................................... 2127
`In Reply
`Stefanos Bonovas, Kalitsa Filioussi, Nikolaos Tsavaris, and Nikolaos M. Sitaras ...................................................................... 2127
`Lipophilic Statins Merit Additional Study for Breast Cancer Chemoprevention
`Tatiana M. Prowell, Vered Stearns, and Bruce Trock ........................................................................................................................................ 2128
`
`(continued on following page)
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`Copyright © 2022 American Society of Clinical Oncology. All rights reserved.
`
`UPenn Ex. 2039
`Miltenyi v. UPenn
`IPR2022-00853
`
`

`

`In Reply
`Stefanos Bonovas, Kalitsa Filioussi, Nikolaos Tsavaris, and Nikolaos M. Sitaras ...................................................................... 2129
`Statins and Breast Cancer Prevention: Time for Randomized Controlled Trials
`Julian R. Sprague and Marie E. Wood .......................................................................................................................................................................... 2129
`In Reply
`Stefanos Bonovas, Kalitsa Filioussi, Nikolaos Tsavaris, and Nikolaos M. Sitaras ...................................................................... 2130
`Decisional Priority in Pediatric Oncology Revisited: Involving Children in
`Decision Making
`Nicolas André ................................................................................................................................................................................................................................... 2131
`In Reply
`Simon N. Whitney, Stacey L. Berg, Angela M. Ethier, Ernest Fruge´ , Laurence B. McCullough,
`and Marilyn Hockenberry ........................................................................................................................................................................................................ 2131
`Hand-Foot Syndrome After Dose-Dense Adjuvant Chemotherapy for Breast Cancer:
`A Case Series
`Aditya Bardia, Charles L. Loprinzi, and Matthew P. Goetz ............................................................................................................................
`Treatment of Metastatic Renal Cell Carcinoma With Autologous T-Lymphocytes
`Genetically Retargeted Against Carbonic Anhydrase IX: First Clinical Experience
`Cor H.J. Lamers, Stefan Sleijfer, Arnold G. Vulto, Wim H.J. Kruit, Mike Kliffen, Reno Debets,
`Jan W. Gratama, Gerrit Stoter, and Egbert Oosterwijk ...................................................................................................................................
`
`e18
`
`e20
`
`Erratum ............................................................................................................................................................................................................................................... 2133
`
`Also in This Issue
`Announcements
`Information for Contributors
`Current Abstracts
`Calendar of Oncology Events
`
`Article was published online ahead of print at www.jco.org
`
`Additional correspondence available online at www.jco.org
`
`www.jco.org
`
`www.asco.org
`
`Downloaded from ascopubs.org by 165.225.9.19 on July 16, 2022 from 165.225.009.019
`
`Copyright © 2022 American Society of Clinical Oncology. All rights reserved.
`
`UPenn Ex. 2039
`Miltenyi v. UPenn
`IPR2022-00853
`
`