Detection and Prostate Cancer Utilizing Monoclonal Antibody J591 and Intraoperative Beta and Gamma Cameras

UNCLASSIFIED AD NUMBER ADB286864 NEW LIMITATION CHANGE TO Approved for public release, unlimited distribution FROM Distribution authorized to agencies only; Proprietary 2001. Other requests shall U.S. Army Medical Research Command, 504 Scott St., Ft. 21702-5012. U.S. Gov't. Info.; Dec be referred to and Materiel Detrick, MD AUTHORITY USAMRMC ltr, 23 Apr 2003 THIS PAGE IS UNCLASSIFIED AD Award Number: TITLE: DAMD17-98-1-8552 Detection of Prostate Cancer Utilizing Monoclonal Antibody J591 and Intraoperative Beta and Gamma Cameras PRINCIPAL INVESTIGATOR: Steven Larson, M.D. Farhad Daghighian, Ph.D. CONTRACTING ORGANIZATION: Sloan-Kettering Institute for Cancer Research New York, New York 10021 REPORT DATE: December 2001 TYPE OF REPORT: PREPARED FOR: Final U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Distribution authorized to U.S. Government agencies only (proprietary information, Dec 01). Other requests for this document shall be referred to U.S. Army Medical Research and Materiel Command, 504 Scott Street, Fort Detrick, Maryland 21702-5012. The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. 20030306 137 NOTICE OR OTHER SPECIFICATIONS, DRAWINGS, USING GOVERNMENT DATA INCLUDED IN THIS DOCUMENT FOR ANY PURPOSE OTHER DOES NOT IN ANY WAY PROCUREMENT THAN GOVERNMENT THE FACT THAT THE GOVERNMENT. THE U.S. OBLIGATE THE DRAWINGS, OR SUPPLIED FORMULATED GOVERNMENT OR OTHER DATA DOES NOT LICENSE THE SPECIFICATIONS, HOLDER OR ANY OTHER PERSON OR CORPORATION; OR CONVEY ANY RIGHTS OR PERMISSION TO MANUFACTURE, USE, OR SELL ANY PATENTED INVENTION THAT MAY RELATE TO THEM. LIMITED RIGHTS LEGEND Award Number: DAMD17-98-1-8552 Organization: Sloan-Kettering Institute for Cancer Research Those portions of the technical data contained in this report marked as limited rights data shall not, without the written permission of the above contractor, be (a) released or disclosed outside the government, (b) used by in the case of computer software for manufacture or, the Government documentation, for preparing the same or similar computer software, or (c) used by a party other than. the Government, except that the Government may release or disclose technical data to persons outside the Government, or (i) such release, permit the use of technical data by such persons, if is a disclosure, or use is necessary for emergency repair or overhaul or (ii) release or disclosure of technical data (other than detailed manufacturing or process data) to, or use of such data by, a foreign government that is in the interest of the Government and is required for evaluational or informational purposes, provided in either case that such release, disclosure or use is made subject to a prohibition that the person to whom the data is released or release or disclose such data, and the disclosed may not further use, contractor or subcontractor or subcontractor asserting the restriction is This legend, together with the notified of such release, disclosure or use. indications of the portions of this data which are subject to such limitations, shall be included on any reproduction hereof which includes any part of the portions subject to such limitations. THIS TECHNICAL PUBLICATION. REPORT HAS BEEN REVIEWED AND IS APPROVED FOR FormApproved REPORT DOCUMENTATION PAGE OMB No. 074-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing Instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503 1. AGENCY USE ONLY (Leave blank) 2. REPORT DATE December 2001 3. REPORT TYPE AND DATES COVERED Final (1 Oct 98 - 30 Nov 01) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Detection of Prostate Cancer Utilizing Monoclonal Antibody J591 and Intraoperative Beta and Gamma Cameras DAMD17-98-1-8552 6. AUTHOR(S) Steven Larson, M.D. Farhad Daghighian, Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER for Cancer Research Sloan-Kettering Institute 10021 New York, New York E*Mail: larsons@mskcc .org 9. SPONSORING I MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSORING / MONITORING AGENCY REPORT NUMBER U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 11. SUPPLEMENTARY NOTES 12b. DISTRIBUTION CODE 12a. DISTRIBUTION I AVAILABILITY STATEMENT Distribution authorized to U.S. Government agencies only Other requests for this (proprietary information, Dec 01). document shall be referred to U.S. Army Medical Research and Materiel Command, 504 Scott Street, Fort Detrick, Maryland 21702-5012. 14. ABSTRACT The hypothesis of this project is that these novel cameras, applied during surgery on prostate cancer patients after being injected by radiolabeled antibody J591, would detect small pieces of cancerous tissue that would otherwise remain undetected. According to our project, a group of prostate cancer patients who are scheduled for surgery, will be injected with radiolabeled J591 mAb. Then our cameras will be used during surgery to locate any involved lymph node, or tissues at the margins of the resected prostate that may be infiltrated by cancer. Also, we planned to use our flexible beta camera to locate the best site in transrectal biopsies using Y-90 labeled mAb. According to our plan, the first year was devoted to development of the novel instrumentation for detection of prostate tumors. This task was successfully completed. The next eighteen months was devoted to testing and characterizing the devices in laboratory and improving them as needed. This task was also successfully completed. 15. NUMBER OF PAGES 14. SUBJECT TERMS prostate cancer, imaging, monoclonal antibody, intraoperative camera 14 16. PRICE CODE 17. SECURITY CLASSIFICATION OF REPORT Unclassified NSN 7540-01-280-5500 18. SECURITY CLASSIFICATION OF THIS PAGE Unclassified 19. SECURITY CLASSIFICATION OF ABSTRACT Unclassified 20. LIMITATION OF ABSTRACT Unlimited Standard Form 298 (Rev. 2-89) Prescribed by ANSI Std. Z39.18 298-102 FOREWORD We have produced a monoclonal antibody that specifically binds to a prostate specific membrane antigen. This compound, called J591, has been labeled with radioactive isotopes In-111 and Y-90. We have developed three novel cameras that are capable of efficiently detecting a wide variety of radioisotopes that emit gamma or beta rays. They are small and can enter the body during open surgery or endoscopic procedures to provide better images in a shorter time, and more importantly, in real time, while the surgery is proceeding. These include: a hand held beta camera, a flexible beta camera, and a hand-held gamma camera. The hypothesis of this project is that these novel cameras, applied during surgery on prostate cancer patients after being injected by radiolabeled antibody J591, would detect small pieces of cancerous tissue that would otherwise remain undetected. According to our project, a group of prostate cancer patients who are scheduled for surgery, will be injected with radiolabeled J591 mAb. Then our cameras will be used during surgery to locate any involved lymph node, or tissues at the margins of the resected prostate that may be infiltrated by cancer. Also, we planned to use our flexible beta camera to locate the best site in transrectal biopsies using Y-90 labeled mAb. According to our plan, the first year was devoted to development of the novel instrumentation for detection of prostate tumors. This task was successfully completed. The next eighteen months was devoted to testing and characterizing the devices in laboratory and improving them as needed. This task was also successfully completed. The clinical trials of the these instruments were delayed due to humanizing the antibody and delays in obtaining IRB approval. Page 3 TABLE OF CONTENTS Front Cover SF 298 Page 2 Foreword Page 3 Table of Contents Page 4 Body Scintillation detector for the gamma camera Trans-rectal beta camera Electronics for beta and gamma cameras Software for image acquisition and display Beta Camera Construction Testing Results of Gamma camera Testing Page 5 Page 7 Page 7 Page 8 Page 10 Page 11 Conclusions Page 12 References Page 12 Publications, Personnel, Graduate Degrees Page 13 Page 4 Task 1) scintillation detector for the gamma camera [Status : Complete] During the past year a novel scintillator, called LSO, was introduced to market by the CTI Corp. We conducted a design research for use of LSO instead of NaI(T1) scintillator. In order to determine imaging performance, light collection response studies were conducted by simulating the response to point light sources whose origin was varied throughout the crystal radially. Optical photon tracking simulations were performed for 60 cm diameter NaI(T1) and LSO disks coupled to a PMT. For the NaI(Tl) a 13 mm thick disk was studied 13.0 mm for 174keV Photons of In-111. For the LSO disk the corresponding thickness was 5.0 mm. The goal of these simulations was to determine the light distribution properties for these crystals. Simulations were performed with a modified version of DETECT [1]. The top surface is painted with a white diffuse Lambertian reflector that preferentially reflects light toward the photo cathode, and all other surfaces are polished for optimal light transmission. The z coordinate or depth of these point sources of light was fixed at the average depth of interaction in that crystal for a given gamma ray energy. The probability that a gamma ray interacts in a crystal decreases exponentially with depth. The mean interaction depth was then calculated using this exponential distribution. For a NaI(Tl) crystal of 13 mm thickness, this average depth is 4.8 mm for 174 keV gamma rays emitted by In-lll. The mean depth was taken as 2.0 mm in the 5.0 mm LSO disk thickness. These point sources of light simulate the effect of a single gamma ray photoabsorption. Results: Figure 1 shows images of the light photon intensity distribution that impinges on the photocathode for a point flash of light consisting of 6600 light photons created in the 13 mm thick NaI(T1) disk (left) and 4600 photons [2] in the 5 mm LSO disk (right). Figure 1. The photon distribution in 13 mm thick, NaI(Tl) (left); and 5 mm thick LSO (right) Studying the fraction of photon transported to the PMT photocathode in NaI(T1) and LSO, demonstrated that even though NaI(T1) has over 40% more light yield, its lower gamma ray stopping power dictates that it must be over a factor of two thicker than an LSO disk of equivalent stopping power, resulting in lower light collection efficiency for the NaI(T1) for these particular configurations. Page 5 The profiles of light distribution at various locations were fitted to Lorentzian distribution. Figure 4 shows plots of the peak position (left) and width (right) of the distributions for NaI(T1) (10 and 13 mm thick) and LSO (3.5 and 5 mm thick) for the 140 and 174 keV energy and the seven source positions. 120 PEAK PIXEL Na1 •.--a'- LOCATION IN m width Na 1103mmwidth L3mm width .... LSO5 mm width I 100 25 • . 80 20 60 -- o Nat(Tt) 10 mm peak pos.a Nal13nmmpeakpos ... LSO 3.5 mm peak pos - 40 as 15 LSO5mmpeakpos "'• .... ..,.... 10 ...... 20 0 5 0 5 10 15 20 25 30 0 5 L 10 L 15 20 L 25 LIGHT SOURCE POSITION (mm) LIGHT SOURCE POSITION (mm) Figure 2. Left, peak locations and right, width of the photon intensity profiles for 140 and 174 keV interactions in the NaI(T1) and LSO disks. The point of maximum intensity for the light distributions (related to event position) in NaI(T1) and LSO follow roughly the same, nearly linear curve for all the radial source distributions. Toward the edge of the detector LSO curve is more linear. The major advantage of LSO is demonstrated in its narrower light spread function (Fig. 2, right). This advantage translates into better spatial resolution compared to that for the NaI(T1). Conclusion: We have simulated light distribution properties in NaI(T1) and LSO disks optimized for the detection of 174 keV gamma rays emitted by In-l 11. The lower gamma ray stopping power of NaI(T1) dictates that it must be over a factor of two thicker than an LSO disk of equivalent stopping power. Thus, even though NaI(TI) has over 40% more intrinsic light yield than LSO, the latter has more desirable properties in terms of higher light transmission (Figure 1) and narrower light spread function (Figure 2, right). Since there is a direct correspondence between scintillation imaging signal-to-noise ratio and light collection efficiency and between spatial resolution and light spread width, we conclude that LSO is the scintillator of choice for this particular application. [Status: Complete] Experimental Evaluation of LSO for camera LSO crystals were purchased from CTI Corp. and were cut and polished to two discs of 60 mm diameter and 3.5 and 5 mm thick. One potential problem in using LSO was the existence of a natural radioisotope of lutetium with long half-life radioactive decay. We measured the intrinsic count rate of a 60 mm diameter, 5 mm thick crystal to be 300 cps Page 6 30 in the energy window of 150-200 keV. Considering that this background noise is evenly distributed over the field of view, and is low compared to the count rates from tumors (by a factor of at least 100), therefore this would not cause any problem in the clinical detection of the tumors. [Status: Completed] Task 2) Trans-Rectal Beta Camera: This instrument is designed to image the distribution of Y-90 labeled antibody against prostate cancer, through the rectal tissue. Several optical fiber bundles were tested to identify the best light transmission. A bundle of fiber optics was identified with a 8 mm diameter, containing 15 fibers per mm. It was bent to a 30 degrees, 15 mm from its tip. The overall length of this imaging-grade fiber bundle is 150 mm. A 0.5 mm thick plastic scintillator was glued at the bent tip of the fiber. Aluminized Mylar (0.05 mm thick) was used to stop the entry of visible light. This imaging-grade fiber bundle transmitted 20% of the scintillation light emissions of the plastic scintillator (420 nm). This fiber bundle was mounted on a novel type of PS-PMT with an area of lxl" (Hamamatsu R7600 C12). The sensitivity of this camera was determined to be 2100 cps/microCi, using a point source of F- 18 in contact with the face of the camera Figure 3: The transrectal beta camera Task 3) Electronic Circuits for the Cameras: Page 7 The cameras utilize Hamamatsu's position sensitive PhotoMultiplier Tube (PS- PMT). The PMT's face is bonded to a plastic scintillator for the beta cameras, and LSO scintillator for gamma camera. The following electronic circuits were designed and built. Analog Section: [Status: Completed] 1) The PMT front end electronics: a) The pre-amplifier circuits required for signal amplification b) The high voltage divider. c) Resistor chains for decoding of the position, and the variable resistors for adjustment of uniformity and enlargement of the field of view. These circuits were designed and built, using surface mount components for compactness, on one small board that is mounted on the back of the PSPMT. This way the gamma camera is contained in a cylindrical housing of 3.5" diameter and 3 "height. Second-level electronics: [Status: Completed] This board further amplifies the signals and integrates them. A discriminator circuit sets the upper and lower energy limits, and only those signals that fall into this window are held for digitization. These levels and the high voltage supply (mounted on this board) are adjusted by software. Once a valid signal is detected, the four identical integrate-andhold circuits operate on the Xa, Xb, Ya, and Yb, signals respectively. This captures the position information. The pulse that is generated also acts as the digitizing pulse for A/D conversion. Digital Electronic Circuits: [Status: Complete] Each signal, Xb, Xb, Ya, Yb, is routed to its own LPTAD8FIFO board. The LPTAD8FIFO is a high speed (>1 MSample/s) 8 bit A/D converter containing up to 64K of onboard FIFO RAM. The LPTAD8FIFO board allows the unattended collection of information from the X-Y PMT with little or no processor overhead. Xb, Ya, and Yb, values are automatically digitized whenever a valid pulse is generated from the detection threshold circuitry. These values are buffered in the FIFO until the FIFO is either unloaded or full. The digitized values are transferred to the CPU of a lap-top computer. Page 8 Figure 4: The gamma camera. The camera weight 7 lb, and has a diameter of 3.6 inches, shielded fom the sides for 250 keV radiation of the In-1 11, the back of the camera is not shielded. A standard operating table pole is needed to hold the camera during operation. [Status: completel Task 4) Software: The software was developed to transfer the digitized signals to the computer, calculate the position and the total energy of the radiation event, form the image, correct the image for uniformity, display it for the'user repeatedly. The following is a summary of the functions preformed by the software: 1) calibration / quality control software offers a menu of available calibration/quality control procedures, leads the user through the required steps, gathers data from the camera for inspection by the user, asks the user to specify or verify the continued validity of current parameters, and finally records the session. 2) setup step recalls stored hardware parameter values (determined during calibration) and sends them to the Data Acqusition section. 3) Data Acquisition. The software forms an image from the four set of numbers received from the FIFO, and correct the image for nonuniformity in gain (using a lookup table accumulated in the calibration proceedure), accumulate the images every 0.1 second and display the sum image every 2 seconds. This process continues until the operator pushes the foot pedal. Then the operator is asked to discard the data (this is the default: by pushing the foot pedal again), or entering the data regarding the region of the imaging. Page 9 4) Data Base. The file name is typed after the image is collected, together with the name of the patient and location that the image was taken. 5) Image analysis: simpele tools such as region of interest and line profile analysis are developed for analysis of the images. ; Port JLPT1 []x tputloRd*Reg ioo __ F ShowFIFO QuadData l DT5ConeCionaJumera: Dl CongurationJ pe . c k Reaister Bit D2TReas D3iaeadack Regthister Bit b D4COpetarti Switch 1: D5OeFriog Switch 2: DGOuperator Syatch 3a torSytph a 4 a C__irl r 8o d High Quanl~iiI't Figur 5: themagnRaiain scroeHadren Cour~er Vaue. I meeValue: 21 0 AýDC Crig Reg 0fhex) F_; 1iý Ce g i n 410oa1 sfwr.Aniaetke ytebeacmr n Reard ReadCitr adýýj 122 Rtte (cps) ADC Cr'g Reg 1 ({lxt AD FFOEmpty. Max Img Cont Tes Utility St Clear Tismng1 Y Ln TeshVnitaievoity f t900J Low Quamlfying f"(W: FI Tshold (mV: a ReatatlusByte System Status Byle (here: ShowTma I Xb 0 mgeU W, Aut&Scale Image Figure 5: the main screen of the camera software. An image taken by the beta camera from a phatom of point sources of F- 18 is also shown. Task 5: Beta Camera Construction and testing (Status: Complete) Figure 6: Beta camera, having a field of view of 22x22 mm. This camera was built by coupling a thin sheet of plastic scintillator was coupled to a PSPMT (Hamamatsu C-i12), the face of the camera is covered by thin aluminized mylar. An image taken by this camera from a phantom of F- 18 point-sources is shown in Figure 4. The sensitivity of this camera for F-i18 was determined to be 3 400 cps/microCi in contact. Page 10 Task 6) Results of the Gamma Camera Tests: (Status: Complete) Figure 6: Image taken by the gamma camera from two point sources of In-1 11. These sources are 2 mm in diameters, 15 millimeters apart from each other. The distance of the camera from the source is 10 mm. The sources are 25. and 5 microCi each. The image was acquired for 60 seconds. The followings are the characteristics of the camera for imaging In-Ill. Physical: The camera weight 7 lb, and has a diameter of 3.6 inches. The camera is shielded from the sides for 250 keV radiation of the In- 11, the back of the camera is not shielded. An standard operating table pole (those that clamp onto the rails of the operating table) should be used to hold the camera. Performance: The spatial resolution at 1 cm from the face of the collimator is 5.5 mm FWHM. The sensitivity at 1 cm from the face of the collimator (in air) is 273 cps per microCi. The field of view is 2 inches in diameter. Page 11 Note: the above sensitivity and resolution is for 174 keV emission of In-111. The software is not capable of acquiring images in two windows simultaneously. Conclusion The research conducted during this project resulted in an important discovery in nuclear imaging technique, namely, the superiority of LSO over NaI(T1). This discovery changed our original design. New scintillator and collimator system was designed and built. The electronic system was also designed and built. The software for image acquisition, display, and analysis was developed. The performance of the instruments developed in this project were determined by phantom studies. More studies with animals and humans are planned in the near future. References: G.F. Knoll, T.F. Knoll, and T.M. Henderson. Light Collection in Scintillation Detector Composites for Neutron Detection. IEEE Trans. Nucl. Sci. 35 (1988) 872-5. [2] M. Moszynsi, M. Kapusta, M. Mayhugh, D. Wolski, S.O. Flyckt. Absolute Light Output of Scintillators. IEEE Trans. Nucl. Sci. 44(3) (1997) 1052-61. [1] Page 12 Publications n/a Personnel Receiving Pay * David Cheng * Farhad Daghighian * Steven Larson * Larry Poon * Michael Reznikov * Pat Zanzonico Graduate Degrees n/a Page 13 DEPARTMENT OF THE ARMY US ARMY MEDICAL RESEARCH AND MATERIEL COMMAND 504 SCOTT STREET FORT DETRICK, MD 21702-5012 REPLY TO ATTENTION OF MCMR-RMI-S (70-1y) 23 Apr 03 MEMORANDUM FOR Administrator, Defense Technical Information Center (DTIC-OCA), 8725 John J. Kingman Road, Fort Belvoir, VA 22060-6218 SUBJECT: Request Change in Distribution Statement 1. The U.S. Army Medical Research and Materiel Command has reexamined the need for the limitation assigned to technical reports written for this Command. Request the limited distribution statement for the enclosed accession numbers be changed to "Approved for public release; distribution unlimited." These reports should be released to the National Technical Information Service. 2. Point of contact for this request is Ms. Kristin Morrow at DSN 343-7327 or by e-mail at Kristin.Morrow@det.amedd.army.mil. FOR THE COMMANDER: Encl PH1 . RINEHART Deputy Chief of Staff for Information Management ADB262329 ADB286864