not for publication or presentation · group that hematopoietic stem cell transplant (hct) was the...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR CELLULAR THERAPIES Tampa, Florida Wednesday, February 11, 2009, 12:15 pm - 2:15 pm Co-Chair: Joshua Hare, MD, University of Miami, Miami, FL Phone: 305-243-1998; Fax: 305-243-1894; E-mail: [email protected] Co-Chair: Helen Heslop, MD, Baylor College of Medicine, Houston, TX

Phone: 832-824-4662; Fax: 832-825-4668; E-mail: [email protected] Co-Chair: Armand Keating, MD, Princess Margaret Hospital, Toronto, Canada Phone: 416-946-4595; Fax: 416-946-4530; E-mail: [email protected] Statisticians: John Klein, PhD, CIBMTR Statistical Center

Phone: 414-456-8379; Fax: 414-456-6530; E-mail: [email protected] Kathleen Sobocinski, MS, CIBMTR Statistical Center

Phone: 414-805-0682; Fax: 414-805-0714; E-mail: [email protected] Scientific Director: Marcelo Pasquini, MD, MS, CIBMTR Statistical Center Phone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected] 1. Introduction

a. Introduction of Leadership Team b. Minutes of February, 2007 meeting (Attachment 1)

2. Accrual Summary (Attachment 2) 3. Data Collection

a. HCT-related Cellular Therapy 1. Registration level: Post TED (Attachment 3) 2. Research forms: DCI section (Attachment 4)

b. Cellular Therapies for Regenerative Medicine (non-HCT indicataions): Cellular Therapy Essential Data (CTED) (Attachment 5)

c. EBMT survey (Attachment 6) 4. Invited Speakers a. Katarina LeBlanc – EBMT Cellular Therapy Working Party Update b. Ann Leen – Virus-specific CTLs

c. Ian McNiece – Cellular Therapy And Cardiovascular Disease 5. Future/Proposed Studies

a. PROP 1208-69 Follow Up of Subjects Receiving Genetically Modified Cell Products Post Transplant (Heslop) (Attachment 7)

b. PROP 1208-72 Survey of Indication of Cellular Therapy (Pasquini) (Attachment 8)

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Not for publication or presentation

6. Issues a. Unique patient ID assignment b. Protocol and consent changes c. DCI forms revisions d. Cellular therapy for GVHD – new form?

7. Other Business

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Not for presentation or publication Attachment 1

M I N U T E S CIBMTR WORKING COMMITTEE FOR CELLULAR THERAPIES Tampa, Florida Saturday, February 10, 2008, 12:15 pm - 2:15 pm Co-Chair: Joshua Hare, MD, University of Miami, Miami, FL Phone: 305-243-1998; Fax: 305-243-1894; E-mail: [email protected] Co-Chair: Helen Heslop, MD, Baylor College of Medicine, Houston, TX

Phone: 832-824-4662; Fax: 832-825-4668; E-mail: [email protected] Co-Chair: Armand Keating, MD, Princess Margaret Hospital, Toronto, Canada Phone: 416-946-4595; Fax: 416-946-4530; E-mail: [email protected] Statisticians: John Klein, PhD, CIBMTR Statistical Center

Phone: 414-456-8379; Fax: 414-456-6530; E-mail: [email protected] Kathleen Sobocinski, MS, CIBMTR Statistical Center

Phone: 414-805-0682; Fax: 414-805-0714; E-mail: [email protected] Scientific Director: Marcelo Pasquini, MD, MS, CIBMTR Statistical Center Phone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

Cellular Therapies Working Group Minutes

San Diego, CA February 14, 2008

Attendees: Juliet Barker (MSKCC) Robert Beatty (HRSA) Michael Boo (NMDP) Claudio Brunstein (University of MN) Nancy DiFronzo (NHLBI) Paul Eldridge (St. Jude Children’s Research Hospital) William Ferguson (St. Louis Cord Blood Bank) James Gajewski (Temple University) Randy Gale (HRSA) Adrian Gee (PACT/FACT) Linda Griffith (DAIT/NIAID) Zafer Gulbas (Eskisehir Osmangazi University, Turkey) Helen Heslop (ASBMT/FACT/PACT/SCCT) Ed Horwitz (ISCT/Children’s Hospital of Philadelphia) Grace Kao (DFCI) Armand Keating (SCCT) Mary Laughlin (ISCT)

Hillard Lazarus (Case Western Reserve) C. F. LeMaistre (Texas Transplant Institute/FACT) Kathy Loper (AABB) John McMannus (MD Anderson) William Merritt (NCI/CTEP) Dietger Niederwieser (EBMT) Ricardo Pasquini (Hospital of Clinics – Brazil) Jerome Ritz (Dana Farber Cancer Institute) Philip Rowlings (Calvary Mater Newcastle, AU) Robert Soiffer (ASBMT/DFCI) Ed Snyder (Yale/NMDP) David Styers (Emmes/PACT) Carolyn Taylor (Medical College of WI) John Wagner (University of MN) Roy Wu (NCI/CTEP)

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Not for publication or presentation Attachment 1

CIBMTR Staff: Mary Horowitz, J. D. Rizzo, Marcelo Pasquini, Carol Doleysh, Kay Gardner, Diane Knutson, Marie Matlack, Paula Watry CIBMTR INTEREST IN CELLULAR THERAPY

− Overview − Mary Horowitz gave a brief introduction to the topic of cellular therapies. She reminded the

group that hematopoietic stem cell transplant (HCT) was the first successful cellular therapy (CT). In 1984, after 10 years of data collection, there were fewer than 5000 cases in the database and today there are large multi-center trials for HCT. Researchers feel we are now in the field of CT where we were in the early 1970’s with HCT. She asked: “Are we willing to make the investment to collect the data on these therapies in a way that we can answer questions in a more sophisticated way in the future?”

− SCTOD requirements

− The C.W. Bill Young Transplantation Program legislation requires that we design a plan to collect data on outcomes of emerging therapies. It was suggested that investigators should go beyond minimum regulatory requirements (which may be interpreted as being restricted to allogeneic transplants) as there is growing international and national regulatory pressure to follow recipients of all types of CT. Even the World Health Organization (WHO) advocates a global knowledge base of tissue transplantation, including CT. Lastly, from a research perspective, most current CT approaches use autologous cells.

Dr. Horowitz recommended that the project include: − a focus on scientific objectives − understanding trends and promising approaches − standardization of outcome information − identification of data fields for collection

− There is now an infrastructure that was not available in the early days of HCT. Having this

model now will be an asset as we move forward in collaboration and with a commitment to harmonize efforts.

− Cellular Therapy Working Committee

− Marcelo Pasquini is taking the lead on this project as the assigned Scientific Director of this new CIBMTR Working Committee. Those wishing to participate in the Committee need only to sign up to receive mailings and participate in future meetings. He stated the objective is to document the activity and study the outcomes of uses of stem cell progenitors or ex vivo manipulated cellular products in patients who undergo procedures other than traditional uses of HCT. Today’s goal was to identify stakeholders who are willing to participate in these early efforts. This committee will help to develop a database to track outcomes and will provide scientific oversight for this project. The expertise within different organizations is needed to begin developing these data collection instruments.

− Current Status of Interactions with other organizations:

− Informal preliminary discussions have been held with: Specialized Centers for Cell-Based Therapy (SCCT), Production Assistance for Cellular Therapy (PACT), American Society for Blood and Marrow Transplantation (ASBMT), International Society for Cellular Therapy (ISCT) and the American Association of Blood Banks (AABB)

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− Cardiovascular Cell Therapy Research Network (CCTRN) – CIBMTR initiated contact with

CCTRN during a Regenerative Medicine Symposium in October where Mary Horowitz gave an overview of CIBMTR history, structure and activities. She invited collaboration in the development of a database for these new CT initiatives. She was then invited to present similar material to their steering committee in January.

− European Group for Blood and Marrow Transplant (EBMT) – There has been preliminary

communication with the EBMT CT Working Party which has already developed a CT form (see meeting attachments); they have enthusiastically expressed interest in collaboration.

GROUP PRESENTATIONS Missions, expertise and ongoing activities were presented by various group representatives. All indicated significant interest in participating in the development of this project. Specialized Centers for Cell-Based Therapy (SCCT) – Armand Keating

− Major initiative of NHBLI – multi-disciplinary, 3 centers funded (Baylor, Johns Hopkins/University of Miami and Massachusetts General)

− Operational support provided by Emmes and NHLBI; organizational structure includes of Steering Committee of principal investigators and the Emmes Corporation

− One of the goals is to foster educational opportunities between centers including interactions between post doctorate fellows and faculty

− There are also basic translational research interactions among centers − Clinical Trials Review:

− Cedar Sinai/ Johns Hopkins: cardiosphere derived cells for recent MI – to activate soon − Johns Hopkins/ University of Miami consortium: Mesenchymal Stem Cells (MSCs) – in

infarct setting, intramyocardial injection during CABG – is accruing − Massachusetts General/Harvard Stem Cell Institute: parathyroid hormone following

sequential unrelated cord blood transplant – centers identified (there is center competition due to similar protocols)

− Massachusetts General/Harvard Stem Cell Institute: parathyroid hormone with chemotherapy in refractory relapsed AML – centers identified

− Baylor: expertise with virus specific CTLs for adenovirus infection post allo transplant - completed

− Baylor: allo depleted T cells transduced with induced test phase 9 suicide gene after haplo (restricted to Baylor)

− Baylor/FHCRC/MDAnderson collaboration: virus specific CTLs for Adenovirus, CMV, EBV post HCT – grant review soon

− SCCT brings “complimentarity” with significant level of expertise and history of close interaction with PACT

International Society for Cellular Therapy (ISCT) – Mary Laughlin

− Involves directors of marrow processing labs internationally − Mission statement: ISCT is the global forum and resource for developing and supporting

innovative cellular therapies through communication, education, and training, thus furthering clinical based investigation for the benefit of patients

− 1300 members in 40 countries, clinical and research based − Membership from: research institutes (27%), universities (25%), industry (25%), hospitals (17%)

and government (7%)

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− Translational focus; work closely with FDA and industry to get ideas from universities into hands of the clinicians and into the marketplace.

− Education, publications, interactive webinars, biannual CT liaison meetings − Expertise with “Regulators” (focus regulatory committees internationally) − ISCT Commercialization Committee: provides network, focus group, identification of issues

relating to market growth; history of partnering − New developments in cardiology/neurology somewhat scattered , ISCT expertise can provide

support in setting of standards, etc Foundation for the Accreditation of Cellular Therapies (FACT) – Fred LeMaistre

− Dedicated to improving quality of programs performing HCT; a voluntary program − First accreditation was in 1997; now over 150 institutions have successfully completed the

process − ASBMT and ISCT are the parent organizations, helped develop standards − Provides accreditation from collection and processing phase to infusion at the patient bedside − Formed a liaison with NetCord to develop standards in cord blood banking − Those active in the field set standards for inspection and accreditation process

American Society for Blood and Marrow Transplantation (ASBMT) – Bob Soiffer

− Membership includes 1600 transplant professionals − Many actively participate in CT research

Production Assistance for Cellular Therapy (PACT) – Adrian Gee

− Funded through a contract by NHLBI − Supports 3 manufacturing facilities that can produce GMP products if institutions can not do it

themselves − Has 40 applications in progress − Educational component includes webinars; book in progress

American Association of Blood Banks (AABB) – Kathy Loper

− Founded in 1947; 8000 individual members; 1800 institutional members in 50 states and 80 countries

− Educate professionals in the field and providing resources, including annual meeting (with 7500 attendees), spring conference, books, publications, newsletters, audio conferences, and distance learning

− Accredit cord blood banks; a resource to the general public − Accreditation on site every 2 years; currently have 105 accredited for HPC, 44 for cord blood

(including 5 of the 8 NCBI banks), 2 somatic cell facilities, 15 in process of accreditation − Set standards; review every 18 months − Possible areas of interest to this group include: national blood survey, the alliance for

harmonization for standardization of cell therapy accreditation, the ISBT128 initiative (the global standard for the identification, labeling and information processing of human blood, tissue and organ products), bio-vigilance (a national centralized system for confidential adverse event reporting in partnership with CDC); data available for studies, benchmarking, analysis

− Blood collection and utilization survey done every two years; includes section on CT; forms could be revised to collect additional data

− AHCTA (Alliance for Harmonization of Cellular Therapy Accreditation): multi-organizational/national initiative; initial work includes import/export requirements and crosswalks between organizations

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European Group for Blood and Marrow Transplant (EBMT) – Dietger Niederwieser

− 502 member teams in Europe, 650 total in 59 countries with more than 30 languages; 3282 members

− Cardiologists/neurologists doing studies; want to be involved with EBMT registry as they don’t have one

− Med A form for CT has been developed (see meeting attachments) − Should harmonize efforts from beginning to save work later − Could present concept to WBMT (Worldwide Bone Marrow Transplant Registry) − Suggest possible discussion with insurance companies; suggest they don’t pay if data not reported

COMMON DATA COLLECTION TOOL Marcelo Pasquini suggested that the highest priority goal now is to design this common data collection tool. A focus group should be identified to take the lead on this project. There was additional discussion on this topic. Highlights include: Defining the scope of form:

− Marrow-derived cells versus other CT − Plan to develop a simple one page form to document the activity; will include all indications,

demographics, recipient, disease, product, limited outcomes; harmonize with existing EBMT tool and make available through FormsNet , then expand the tool as CT field expands.

− Consider modular form approach; now just determine that something happened − The legislation does not provide guidance as to scope of project − Effective January 2008, all clinical trails (including Phase I) must be registered; also required

higher level of reporting to FDA − Where to start: − Cardiovascular field is currently engaged in most studies; would be a good place to start; would

not, however, stop others from providing information − Should collect autologous and allogeneic information − Suggested roll-out: start form for cell processing labs and cord blood banks, then expand to

cardiology groups, then other regenerative medicine areas. Slowly expand rather than worry where to draw the line

− Must keep form simple − Having right people on project more important than right form at this time − Obtain further information on number of units used for regenerative medicine − Use whatever data can get; will not be comprehensive at first, but will evolve − Need a form first before others become willing to participate − Needs to be driven by leaders in the field; need a “critical mass” of interested parties − Must “decide to start”; track activity first; eventually can consider registry studies

Challenges:

− No motivation to provide data as centers will want to publish their own data − Attracting investigators to contribute to a database; cannot impose on people − Who completes form (physician vs data manager)? In HCT, graft information comes from the

cord blood bank, not transplant center. In CT, PACT (or cell lab) could provide product information; physician infusing cells must also provide information

Other possible contacts:

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− Companies involved in the field − American College of Surgeons − SBIR, STTR committees funded by NIH – represent small biotech companies working with

investigators − Incentives: funding and regulation (many under IND)

− www.clinicaltrials.gov –see what’s being done and start contacting investigators − Governing bodies funding groups/projects; encourage them to support data submission

requirement − Regenerative Medicine: next scheduled meeting in December; could have booth and data

collection form available − Hospital departments of Surgery or Radiology (interventionalists) − Funding agencies (government): start with the willing

Suggested Timeline:

− 1/08 – begin drafting data elements/fields − 3/08 – representative group meet, finalize draft form − 4/08 – harmonize efforts with EBMT CT activities − 5/08 – target for release of CT data collection forms

Action items:

− Identify group willing to develop form and to make contacts − Volunteers include Philip Rowlings, Adrian Gee, Ed Horwitz, Helen Heslop, Kathy Loper,

Sergio Giralt, Armand Keating − CIBMTR will coordinate getting group together − Invite representative(s) from cardiovascular groups to participate

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Accrual Summary for Cellular Therapies Working Committee

Characteristics of patients receiving donor cellular infusion posttransplant registered with ther CIBMTR between 1990 and 2007.

N (%)a

Variable Median (range)b

Number of patients 1609Number of centers 150Age 0-9 131 ( 8) 10-19 148 ( 9) 21-29 185 (12) 31-39 259 (16) 41-49 325 (20) 51-59 386 (24) 61-69 167 (10) 70+ 8(<1)Male sex 950 (59)Primary disease AML 527 (33) ALL 149 ( 9) CML 236 (15) Other leukemias 108 ( 7) MDS 148 ( 9) NHL 164 (10) Hodgkin’s disease 56 ( 3) Plasma Cell Disorders 107 ( 7) Other malignancies 38 ( 2) Severe Aplastic Anemia 17 ( 1) Other non-malignancies 59 ( 4)Year of transplant 1987-1989 9 (<1) 1990-1994 46 ( 3) 1995-1999 198 (12) 2000-2004 925 (57) 2005-2007 431 (27)WHO region Africa 3 (<1) Americas 1156 (72) Eastern Mediterranean 20 ( 1) Europe 342 (21) SE Asia 18 ( 1) Western Pacific 70 ( 4)

a For categorical variables b For continuous variables

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Accrual Summary for Cellular Therapies Working Committee

Indications for cellular therapy registered with the CIBMTR between 2004 and 2007 by year of therapy.

Indication N (%) Acute myocardial infarction 2006 4 (57) 2007 3 (43) Cardiac 2004 2 (17) 2005 1 ( 8) 2006 4 (33) 2007 5 (42)

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CIBMTR/EBMT/EUROCORD/FACT/NMDP Transplant Esential Data US OMB Control No: 0915-0310, Expiration Date: 10/31/2010 Post-TED (10/07) Page 1 of 2

CENTER IDENTIFICATIONCIBMTR Center # __________ EBMT Code (CIC) _______________Hospital: _________________________________________________Unit (circle)*: A H O P Other, specify: ____________________

Contact person: ___________________________________________Phone #: ______________________ Fax #: ____________________Email: ___________________________________________________

Date of this Report:___ ___ ___ ___ - ___ ___ - ___ ___ Changed Y Y Y Y M M D D

Day 100 6 months Annual FU visit (___ ___ yr post-HSCT)Did the recipient receive a subsequent HSCT since the date of contact from the last report? Yes No

RECIPIENT IDENTIFICATIONCIBMTR recipient ID#: _______________________________________Date of Birth:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

Gender: Male FemaleDisease: __________________________________________________

HSCTDonor Type: Allogeneic AutologousChronological # of this: HSCT#: ___ ___ DCI#: ___ ___Date of HSCT for this follow-up:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

Yes No 100 Day Report Only Is 'Date of HSCT' same as date given on Pre-TED? Was HSCT Infusion given? If No,: At least 1 dose of the prep regimen was given? If Yes,: Patient died during prep regimen? This HSCT is cancelled? This HSCT is postponed?

New estimated date: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

INITIAL ANC RECOVERY Was ≥0.5 x 109/L achieved for 3 consecutive labs?** Yes, fi rst date of 3 labs: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D** No, last assessment: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

** Never below Previously reported UnknownDid graft failure occur? Yes No

INITIAL PLATELET RECOVERY(Optional for Non-U.S. Centers)

** Yes, date Platelet >20 x 109/L: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D** No, last assessment: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

** Never below Previously reported Unknown

GRAFT VERSUS HOST DISEASE (Allo only) Maximum Grade of Acute GVHD** 0 I II III IV Present, grade unknown

Maximum extent of Chronic GVHD during this period:** None Limited Extensive Unknown** Date of diagnosis of chronic GVHD: ** ___ ___ ___ ___ - ___ ___ - ___ ___ Continued from last report Y Y Y Y M M D D All Abbreviations on Pre-TED, pg 2

DID A NEW MALIGNANCY, LYMPHOPROLIFERATIVE OR MYELOPROLIFERATIVE DISORDER OCCUR?

Different from the disease for which HSCT performed (not recurrence or transformation).

Yes No Unknown, If yes:Date of diagnosis: ___ ___ ___ ___ - ___ ___ - ___ ___

Y Y Y Y M M D D Acute myeloid leukemia (AML/ANLL) Other leukemia (including ALL), specify:__________________ Breast cancer Central nervous system (CNS) malignancy (glioblastoma,

astrocytoma) Clonal cytogenetic abnormality without leukemia or MDS Gastrointestinal malignancy (colon, rectum, stomach, pancreas,

intestine) Genitourinary malignancy (kidney, bladder, ovary, testicle,

genitalia, uterus, cervix) Hodgkin disease Lung cancer Lymphoma or lymphoproliferative disease

Melanoma Other skin malignancy (basal cell, squamous) Myelodysplasia (MDS)/myeloproliferative (MPS) disorder Oropharyngeal cancer (tongue, buccal mucosa) Sarcoma Thyroid cancer Other malignancy, specify:____________________________

Copy of pathology report/documentation attached? Yes No

Is the tumor EBV positive? Yes No Unknown

REGISTRY USE ONLYDate Received:____________________________ DE:____________

SURVIVALSurvival status at latest follow-up:

Alive Dead Lost To Follow-Up (LTF) Latest follow-up: Last known date alive: ___ ___ ___ ___ - ___ ___ - ___ ___ Day of the month Y Y Y Y M M D D Main cause of death (check only one main cause):

Relapse/Progression/Persistent disease HSCT related causes (check as many as appropriate):

GVHD Pulmonary toxicity Cardiac toxicity Rejection/Poor graft function Infection VOD Other:________________

New malignancy Other:______________________________________________ Unknown

is estimated

POST-HSCT THERAPY (Optional for Non-U.S. Centers) Yes Masked Trial No UnkFGF (velafermin)? Imatinib mesylate (Gleevec, Glivec)?** KGF (palifermin, Kepivance)?**

HSCT FOR NON-MALIGNANT DISEASE ONLY

DCI given in this period? Yes, also complete 'DCI' section on pg 2 No, send only pg 1

Post-Transplant Essential DataNote: “>100 Days Report” answer since last report

= symbol for answer that is only valid on >d100 evaluation.

* Abbreviations, see Pre-TED, pg 2


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CIBMTR/EBMT/EUROCORD/FACT/NMDP Transplant Esential Data US OMB Control No: 0915-0310, Expiration Date: 10/31/2010 Post-TED (10/07) Page 2 of 2

DONOR CELLULAR INFUSION (DCI)

Date of fi rst DCI: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

Total # DCI in 10 weeks______ Type of cell(s) (check all that apply):

Lymphocytes Fibroblasts Dendritic cells Mesenchymal Other, specify:____________________

Indication: Treat GVHD Planned Mixed Chimerism Treat disease Loss/Decreased Chimerism Treat PTLD, EBV-Lym Other, specify: Treat viral ___________________________

Maximum Grade of Acute Graft Versus Host Disease** (GVHD): 0 I II III IV Unknown

If another DCI was received in this reporting period, disease status before next DCI: CR Not in CR Not assessed

Date of second DCI: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D






Date of third DCI: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D






Were there more than 3 instances of DCI infusions in this reporting period? Yes No

If yes, copy this page and continue numbering fourth, fi fth, etc.

MALIGNANT DISEASE EVALUATION FOR THIS HSCT(non-malignant disease skip disease evaluation)

WAS A CR EVER ACHIEVED IN REPONSE TO HSCT(including any therapy planned as of Day 0, excluding any change in therapy in response to disease assessment)?

** Recipient already in CR at start of preparative regimen (N/Apl) ** Yes, post-HSCT CR achieved, date: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D** First CR date reported previously** No, never in CR from HSCT, date assessed: ___ ___ ___ ___ - ___ ___ - ___ ___** Not evaluated Y Y Y Y M M D D

FIRST RELAPSE OR PROGRESSION AFTER HSCT (in this period, any type, not persistent disease)

Yes, answer all 3 methods. If used, give the date used and the results. No––(skip to ‘Additional Treatment’ below)

Relapse/progression detected by molecular method: Yes, Date fi rst seen:___ ___ ___ ___ - ___ ___ - ___ ___

Y Y Y Y M M D D No, Date of Assessment:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D Previously reported Not evaluatedRelapse/progression detected by cytogenetic/FISH method:

Yes, Date fi rst seen:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D No, Date of Assessment:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D Previously reported Not evaluatedRelapse/progression detected by clinical/hematological method:

Yes, Date fi rst seen:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D No, Date of Assessment:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D Previously reported Not evaluated

If a previous HSCT was performed for a different disease than this HSCT, give status of original disease and date determined:

CR Not in CR Date:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

Post-Transplant Essential DataNote: “>100 Days Report” answer since last report

If yes, was the status considered a disease relapse or progression? Yes No

ADDITIONAL TREATMENT? Yes No––(skip to ‘Method’ below)

Yes No * DCI (allo only) (also complete ‘DCI’ section)

Planned (given regardless of disease status/assessment post-HSCT) Not planned (given for relapse, progression, or persistent disease)

METHOD OF LATEST DISEASE ASSESSMENT(record most recent of each)

* In some circumstances, disease may be detected by molecular or cytoge-netic testing, but may not be considered a relapse or progression. It should still be reported. Disease detected? Method No Yes Not evaluated Molecular*

Date latest assessed:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D Cytogenetic/FISH*

Date latest assessed:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D Clinical/Hematologic Date latest assessed:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

= symbol for answer that is only valid on >d100 evaluation.

Report represents: Day 100 6 months Annual CIBMTR Recipient ID#:CIBMTR Center #:

If yes, was the status considered a disease relapse or progression? Yes No


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CENTER IDENTIFICATIONCIBMTR Center # ___________EBMT Code (CIC) ________________Hospital: _________________________________________________Unit: Adult Hematology Oncology Pediatric

Cardiovascular Other ___________________________Contact person: ____________________________________________Phone #: ______________________ Fax #: _____________________Email: ___________________________________________________Date of this Report:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

Cellular Therapy Essential Data – Alternative (CTED-A)

CIBMTR/EBMT Cellular Therapy Esential Data CTED-A (5/20/08) Page 1 of 2

RECIPIENT IDENTIFICATIONUniversal Recipient ID: ______________________________________ID assigned by: CIBMTR EBMT Other _________________ PACT Protocol # ___________________________________________Gender: Male FemaleDate of Birth:___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

INDICATION FOR TREATMENTReason cellular therapy was performed:

New disease indication Disease previously treated with Cellular Therapy

If the patient required conditioning regimen prior to infusion of bone marrow derived cells—STOP fi lling out this form and

refer to the CTED manual for instructions.

Specify indication: Continuing treatment Re-occurrence of the primary disease

CELLULAR THERAPYStatus of primary disease at the time of cellular therapy:

Acute disease Acute exacerbation of chronic disease Chronic disease

Source of donor cells: Autologous Allogeneic

Cellular product use: Single-patient use Multiple-patient use (cell lines)

Cellular product tissue source:Hematopoietic sources

Bone marrow Cord blood Peripheral blood

Non-hematopoietic sources Adipose tissue Amniotic fl uid Cardiac tissue Hepatic tissue Neuronal tissue Ophthalmic tissue Pancreatic tissue Placenta Umbilical cord Other source, specify ___________________________________ Adipose progenitor cells Cardiac progenitor cells CD34+ enriched cells T-Lymphocyte

(Continued on next column)

CELLULAR THERAPY (continued)Cellular product(s):

Dendritic cells Endothelial progenitor cells Human umbilical cord perivascular (HUCPV) cells Islet cells Mesenchymal stromal cells Natural Killer cells Unselected mononuclear cells Other cell type(s), specify________________________________

CELLULAR INFUSIONRoute of cellular infusion:

Intramuscular Intraperitoneal Intrarterial

Intrathecal Intravenous Locally in the tissue

Other route, specify ____________________________________Total number of cellular infusions administered in the period of 3 months from the fi rst infusion: _______________________________________Median number of cells infused per administration: _____ /kg /m2 (circle one)Total number of cells infused in the period of 3 months from the fi rst infusion: _______________ /kg /m2 (circle one)Another procedure performed associated w/cellular therapy (e.g., coro-nary artery bypass surgery, coronary stent placement, decompression of spinal cord injury, matrix implant)?

Yes No Unknown If yes, specify procedure: _______________________________

Did recipient experience any infusion reactions? Yes No Unknown If yes, specify severity:

Mild – transient reaction requiring no treatment or treatment with oral medication

Moderate – symptomatic reaction requiring parenteral medication

Severe – life-threatening or anaphylaxis

Specify artery: Coronary Femoral Other artery, specify_______________________________________

Specify local site: Heart Liver Bone Other site (organ/tissue), specify_____________________________

CLINICAL STATUS OF PARTICIPATIONRecipient participation on clinical trial:

Yes No If yes, specify:

Phase I Phase II Phase III

Single Institution Multi-center

CELLULAR PRODUCT MANIPULATIONManipulation of the cellular product performed:

Yes No Unknown If yes, specify ex-vivo manipulation(s):

Growth factor, specify ______________________________ Cell selection, specify ______________________________ Cell expansion, specify _____________________________ Viral transfection, specify ____________________________ Non-viral transfection, specify ________________________ Other manipulation, specify __________________________

Specify: Living donor Cadaveric donor

Specify: Mobilized product Non-mobilized product

Specify: Blinded Randomized Placebo controlled


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CIBMTR/EBMT Cellular Therapy Esential Data CTED-A (5/20/08) Page 2 of 2

CIBMTR Recipient ID#:CIBMTR Center #:

Select the Specifi c Disease indication for Cellular Therapy:

NEUROLOGIC

Acute Cerebral Vascular Ischemia Amiotrophic Lateral Sclerosis Multiple Sclerosis Myasthenia gravis

DISEASES

Parkinson's Disease Spinal Cord Injury Other Neurologic Disease indication, specify:_____________________

MUSCULOSKELETAL

Avascular Necrosis of Femoral Head Osteoarthritis Osteogenesis Imperfecta

DISEASES

Traumatic Joint Injury Other Musculoskeletal Disease indication, specify:_____________________

AUTOIMMUNE

Rheumatiod Arthritis Systemic Lupus Erythematous Systemic Sclerosis Diabetes Mellitus type 1

DISEASES

Crohn's Disease Ulcerative Colitis Other Autoimmune Disease indication, specify:_____________________

RESPONSE TO CELLULAR THERAPYBest clinical/biological response to cellular therapy?

Complete response or normalization of organ function Partial response or partial normalization of organ function Any response, followed by disease progression No response Disease progression or worsening of organ function Unknown

Organ functioning for response agreement to cellular therapy (Laboratory Radiology or other)?

Yes No Unknown If yes, specify:

Organ function parameter ______________________________Response: Improved Normalized Unchanged Worse

SURVIVALRecipient's survival status at time of this report?

Alive, specify date of most recent follow-up: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

Dead, specify: date of death: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

and main cause of death:

Lost to follow-up, specify last known date alive: ___ ___ ___ ___ - ___ ___ - ___ ___ Y Y Y Y M M D D

Disease relapse/progression/persistent disease Related cell therapyOther cause, specify______ _______________________Unknown

Day of the month is estimated

CARDIOVASCULAR

Acute Myocardial Infarction

Chronic Coronary Artery Disease (Ischemic, Cardiomyopathy)

Heart Failure (Non-ischemic etiologies)

Other CV indication, specify:____________________

Limb Ischemia

Thromboangiitis obliterans

Other Peripheral Vascular Disease indication, specify:_____________________

DISEASES Baseline (Prior to cellular therapy) Organ function parameters: Ejection Fraction: ____________% measured by (circle one): 2D-Echocardiogram or MUGA or MRI

Left Ventricular End-Dyastolic volume: ______________mL

Left Ventricular End-Systolic volume: ______________mL

Number of previous infarcts:_____________________

New York Heart Association Functional Classifi cation (circleone): Class I or Class II or Class III or Class IV

Canadian Cardiovascular Societry Angina Classifi cation (circle one): Class I or Class II or Class III or Class IV

Mean Ankle-Brachial Pressure Index:___________________

Other Baseline Parameter, specify:_____________________

OTHER

Wound Healing Other Disease indication, specify:_____________________

DISEASES


18


19


Study Proposal 1208-69

Study Title: Follow Up of Subjects Receiving Genetically Modified Cell Products Post Transplant Helen Heslop, Baylor College of Medicine, Houston, TX Armand Keating, Princess Margaret Hospital, Toronto, CANADA Edwin Horwitz, Children’s Hospital of Philadelphia, Philadelphia, PA Specific Aims: The genetic modification of hematopoietic progenitor cells (HPC) could theoretically correct many single gene defects of marrow derived cells. Advantages of using hemopoietic progenitors as targets for gene transfer include easy procurement and manipulation ex vivo and the possibility of gene transfer to multiple cell lineages. Initial studies of gene transfer to treat inherited disorders yielded disappointing results because of low transfer to HPC. However a number of gene marking studies produced useful information about marrow reconstitution and source of relapse post transplant. In addition several studies explored approaches to enhance immune reactivity post transplant using either gene modified stem T cells or tumor vaccine approaches. A clinical gene therapy trial in France for the treatment of X-linked Severe Combine Immunodeficiency1 produced encouraging results with recovery of immune function and positive selection of transduced cells. However four children in this trial with X-linked severe combined immunodeficiency (SCID-X1) treated with autologous CD34+ selected stem cells transduced with common γ-chain subsequently developed T cell lymphoproliferation as a result of insertional mutagenesis to the LMO2 proto-oncogene.2;3 More recently one patient in an English study has also developed T cell lymphoblastic lymphoma.4 The FDA initially addressed the risks of tumorigenesis from retroviral vectors over 10 years ago when they requested 15 year follow-up of all gene therapy subjects who participated in clinical trials. Hence, all recipients of gene transfer vectors now require long-term follow-up, including genetic analysis of any tumors that may appear. However no long-term follow up database currently exists for patients who received retroviral transduced cells. Many patients who have received gene-modified cells have done so either with in conjunction with a transplant or as adjuvant cellular therapy post transplant. The established database and data collection methodologies of CIBMTR offer a means of collecting long term follow up data on the subset of patients who received gene modified cells at the time of or post transplant. We propose the following aims in order to obtain follow up data on the 200 or so patients whose data will be available in this registry. 1. To design data collection instruments to collect gene transfer specific information. CIBMTR already

has forms that collect transplant specific information and long term follow up data which would be pertinent to follow up of gene transfer patients. However to collect follow up information on gene transfer patients we will need to design an initial form to collect specific information about the vector used for gene transfer, transduction conditions and target cell. Specific issues for long term follow up include results of RCR assays, development of secondary malignancies and development of new hematologic or neurological complications.

2. To use these forms in conjunction with standard CIBMTR collection forms to obtain detailed follow

up data on patients who received retroviral gene modified cells with or following transplant.

20

Note for publication or presentation Attachment 7

Scientific Justification: Safety is clearly an important consideration in gene transfer studies and the cases of secondary leukemia in the French study have sensitized investigators and public alike to the potential dangers of gene transfer vectors and in particular insertional mutagenesis which is a potential consequence of any integration event, regardless of the vector used. 5 This risk is likely to be small: for example, gene marking studies have been performed with murine retroviruses in more than 100 patients, some of whom have more than 10 years of follow-up.6;7 While most integration events of the vector DNA presumably harmless, there is an unknown (albeit low) risk that in some cases the integration event may result in activation of neighboring gene, such as an oncogene, which could result in uncontrolled cell division or "insertional mutagenesis". Since tumorigenesis is thought to be a multi-step phenomenon, it would be likely that an additional event would be required before a vector insertion at a given locus would result in tumor formation. Although the FDA mandates that all gene transfer patients be followed for long term adverse effects there is very little published data on long term follow up. After the development of T cell lymphoproliferation in the French patients, the American Society of Gene Therapy convened an ad hoc committee to review data from human trials involving retroviral mediated gene transfer to hematopoietic stem cells. They identified 40 clinical trials with at least 232 subjects and collected some preliminary data on these subjects.8 The conclusion of their report was “In performing this data collection effort, it is apparent that there is not a standard format used among the different trials for quantification of cell numbers, measurement of gene transfer in the grafted cells, duration of follow up etc. It would greatly facilitate future efforts to analyze trial results if some uniformity could be adopted. Patient Eligibility Population: Number of Patients To determine the number of patients receiving gene modified cells we have performed a preliminary search of the RAC database of trials and selected studies where the patients received gene modified cells at the time of transplant or post transplant. We identified over 30 studies with an accrual of over 250. There is therefore at least this number of patients in the CIBMTR database on whom long term follow data could be obtained. We emphasize that we are underestimating the number of patients as accrual data is not available on all studies and studies outside the US are not on the RAC database although many overseas centers report to the CIBMTR. The appended tables show studies associated with transplant where patients should be on the CIBMTR database Data Collection: The CIBMTR already has forms that collect transplant specific information and long term follow up data which would be pertinent to follow up of gene transfer patients. However to collect follow up information on gene transfer patients we will need to design an initial form to collect specific information about the vector used for gene transfer, transduction conditions and target cell. Specific issues for long term follow up include results of RCR assays, development of secondary malignancies and development of new hematologic or neurological complications. Study Design (Scientific Plan): 1. Characteristics of the Genetically Modified Product

Information will include details of the target cell, the gene transfer vector used, the number of doses and cell dose administered and delivery method. Specific vector details such as the packaging cell line and construct will also be collected as well as details of transduction methodology.

21


2. Patient Outcome Data Many outcome measures such as survival will already be collected in current CIBMTR data collection instruments. We propose to develop and insert that will collect data pertinent to gene transfer which will include any adverse events attributable to gene transfer and gene transfer safety specific surveillance tests such as RCR assays.

3. Long term follow up

An important issue is the long term consequences of gene transfer. The CIBMTR already has instruments for collecting data on long term outcome of transplant patients and development of complications such as secondary malignancy. We propose to modify these forms to ensure that information pertinent to all long term consequences of gene transfer is captured.

Statistical analysis would primarily be descriptive but would include survival estimates and a possible comparison with matched patients who did not receive genetically modified cells.

References: 1. Hacein-Bey-Abina S, Le Deist F, Carlier F et al. Sustained correction of X-linked severe combined

immunodeficiency by ex vivo gene therapy. N.Engl.J Med 2002;346:1185-1193. 2. Hacein-Bey-Abina S, von Kalle C, Schmidt M et al. A serious adverse event after successful gene

therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348:255-256. 3. Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: are we there

yet? J Clin Invest 2007;117:1456-1465. 4. Howe SJ, Mansour MR, Schwarzwaelder K et al. Insertional mutagenesis combined with acquired

somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest 2008

5. Donahue RE, Kessler SW, Bodine D et al. Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J Exp Med 1992;176:1125-1135.

6. Brenner MK, Heslop HE. Is retroviral gene marking too dangerous to use? Cytotherapy. 2003;5:190-193.

7. Gottschalk S, Rooney CM, Heslop HE. Post-Transplant Lymphoproliferative Disorders. Annu.Rev.Med 2005;56:29-44.

8. Kohn DB, Sadelain M, Dunbar C et al. American Society of Gene Therapy (ASGT) ad hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells. Mol.Ther. 2003;8:180-187.

The following tables show studies associated with transplant where patients should be on the IBMTR

database

22


Marking Studies in Autologous Transplantation using hemopoietic progenitors as the target cell HGT Study Number

Study Site Principal Investigator

Target Cell Disease Number of

patients treated

Reference

4 St Jude Children’s Research Hospital

Brenner

Marrow mononuclear cells

Pediatric AML 12 1-3

5 and 6 St Jude Children’s Research Hospital

Brenner


Neuroblastoma 9 4

7 MD Anderson Cancer Center

Deisseroth


Chronic myeloid leukemia

10 5

14 University of Indiana

Cornetta Marrow mononuclear cells

AML and ALL 5 6

23, 24, 25

NIH Dunbar CD34 selected blood and marrow cells

Breast cancer, myeloma, CML

21 7,8

27,28 Fred Hutchnison Cancer Research Institute

Schuening CD34 selected PB cells

Breast cancer, Hodgkin’s or Lymphoid malignancies

7

30 MD Anderson Cancer Center

Deisseroth CD34 selected blood and marrow cells

Indolent B cell neoplasms

3 9


Brenner (now Bowman)


Neuroblastoma 5 {Rill, Santana,

et al. 1994 ID: 1125


Brenner (now Horwitz)


Pediatric AML 15 3

76/159 St Jude Children’s Research Hospital

Heslop Expanded marrow and blood mononuclear cells

Pediatric solid tumors

0

92 University of Southern California

Douer CD34 selected blood and marrow cells

Breast or lymphoma

1

106/177 University of Minnesota

Verfaillie Cytokine primed CD34 cells

CML 12

297 Baylor College of Medicine

Krance Marked CD34 cells Multiple sclerosis

0


Bowman Marked CD34+ cells Solid tumors 0

304 Karmanos Cancer Institute

Baynes CD34 cells Breast cancer (adeno p53 to purge)

336 Indiana Smith Cord blood CD34 expanded

Post allo tranplant

23


Continued. HGT Study Number


Target Cell Disease Number of

patients treated

Reference

337 CHLA Kohn Cord blood CD34 ADA deficiency

341 NIH Tisdale PBSC HIV 446 St Jude Children’s

Research Hospital Sorrentino CD34 HSC JAK3

deficiency

Transfer of drug resistance genes with autologous transplantation

HGT number


Target Cell Disease Patients Reference

44, 77 MD Anderson cancer Center

Deisseroth (Now ?)

HSC Ovarian, breast 24 10

51 Columbia University Hesdorffer HSC Advanced cancer

5 11

54 NCI O’Shaunessy HSC Breast cancer 6 12 143 NCI Cowan HSC Breast 10 13 172 University of Indiana Abonour/Corne

tta HSC Germ cell

tumors 18 14

173 University of Indiana Williams HSC Brain tumors Unknown 188 University of

Minnesota Verfaillie HSC CML Unknown

265 Western Reserve University

Gerson HSC Advanced tumors

Unknown

24


Transfer of gene modified T cells after allogeneic transplantation

HGT number


Target Cell Disease Number of patients

Reference

17 Fred Hutchinson Cancer Research Center

Riddell CD8 HIV specific T cells

HIV patients undergoing allo BMT

Unknown


Heslop EBV specific cytotoxic T lymphocytes

Post T cell depleted allogeneic bone marrow transplant

26 15-17

129 St Jude Children’s Research Hospital/Baylor College of Medicine

Heslop EBV specific cytotoxic T lymphocytes

Hodgkin’s disease

7 18

107 University of Arkansas

Munshi Tk-transduced T cells for therapy of relapse

Relapsed myeloma

5

146 Iowa/ Northwestern

Link Tk-transduced T cells for therapy of relapse

Relapsed leukemia

11

241 Multicenter Bensinger Tk-transduced T cells for therapy of relapse

Relapsed hematologic malignancy

Unknown

308 Fred Hutchinson Cancer Research Center

Warren CD8 minor Hag specific cells

Relapse of ALL or AML

Unknown

332 City of Hope Jensen CTLs specific for CD20

CD20 lymphoma post BMT

Unknown

364 University of Alabama

Lucas EBV/CMV specific fo CTL

CMV/EBV specific CTL

Baylor College of Medicine

Brenner GD2-CAR transduced T cells

Most post autograft for neuroblastoma

14 19

Tumor vaccines post BMT

HGT number



Reference

319 Baylor College of Medicine

Brenner Fibroblasts AML, ALL 10 20

Baylor College of Medicine

Brenner Neuroblastoma Neuroblastoma 21 21

435 Johns Hopkins Borello Allogeneic GMCSF producing line

Myeloma

25


Mesenchymal Cells

HGT number



Reference


Horwitz Stromal cells Osteodysplasia after allo BMT for OI

6 22

References: 1. Brenner MK, Rill DR, Moen RC et al. Gene-marking to trace origin of relapse after autologous

bone marrow transplantation. Lancet 1993;341:85-86. 2. Brenner MK, Rill DR, Holladay MS et al. Gene marking to determine whether autologous marrow

infusion restores long-term haemopoiesis in cancer patients. Lancet 1993;342:1134-1137. 3. Heslop HE, Rill DR, Horwitz EM et al. Gene marking to assess tumor contamination in stem cell

grafts for acute myeloid leukemia. In: Dicke KA, Keating A, eds. Autologous Blood and Marrow Transplantation. Charlottesville, VA: Carden Jennings; 1999:513-520.

4. Rill DR, Santana VM, Roberts WM et al. Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells. Blood 1994;84:380-383.

5. Deisseroth AB, Zu Z, Claxton D et al. Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML. Blood 1994;83:3068-3076.

6. Cornetta K, Srour EF, Moore A et al. Retroviral gene transfer in autologous bone marrow transplantation for adult acute leukemia. Hum.Gene Ther. 1996;7:1323-1329.

7. Dunbar CE, Cottler-Fox M, O'Shaunessy JA et al. Retrovirally marked CD34-enriched peripheral blood and marrow cells contribute to long term engraftment after autologous transplantation. Blood 1995;85:3048-3057.

8. Emmons RV, Doren S, Zujewski J et al. Retroviral gene transduction of adult peripheral blood or marrow- derived CD34+ cells for six hours without growth factors or on autologous stroma does not improve marking efficiency assessed in vivo. Blood 1997;89:4040-4046.

9. Bachier CR, Giles RE, Ellerson D et al. Hematopoietic retroviral gene marking in patients with follicular non- Hodgkin's lymphoma. Leuk Lymphoma 1999;32:279-288.

10. Hanania EG, Giles RE, Kavanagh J et al. Results of MDR-1 vector modification trial indicate that granulocyte/macrophage colony-forming unit cells do not contribute to posttransplant hematopoietic recovery following intensive systemic therapy. Proc Natl Acad Sci USA 1996;93:15346-15351.

11. Hesdorffer C, Ayello J, Ward M et al. Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation. J Clin Oncol 1998;16:165-172.

12. Moscow JA, Huang H, Carter C et al. Engraftment of MDR1 and NeoR Gene-Transduced Hematopoietic Cells After Breast Cancer Chemotherapy. Blood 1999;94:52-61.

13. Cowan KH, Moscow JA, Huang H et al. Paclitaxel chemotherapy after autologous stem-cell transplantation and engraftment of hematopoietic cells transduced with a retrovirus containing the multidrug resistance complementary DNA (MDR1) in metastatic breast cancer patients [see comments]. Clin Cancer Res 1999;5:1619-1628.

14. Abonour R, Williams DA, Einhorn L et al. Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells [In Process Citation]. Nat Med 2000;6:652-658.

26


15. Rooney CM, Smith CA, Ng C et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr virus-related lymphoproliferation. Lancet 1995;345:9-13.

16. Heslop HE, Ng CYC, Li C et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nature Medicine 1996;2:551-555.

17. Rooney CM, Smith CA, Ng CYC et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 1998;92:1549-1555.

18. Bollard CM, Aguilar L, Straathof KC et al. Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin's Disease. J.Exp.Med. 2004;200:1623-1633.

19. Pule MA, Savoldo B, Myers GD et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat.Med. 2008;14:1264-1270.

20. Rousseau RF, Biagi E, Dutour A et al. Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood 2006;107:1332-1341.

21. Rousseau RF, Haight AE, Hirschmann-Jax C et al. Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood 2003;101:1718-1726.

22. Horwitz EM, Gordon PL, Koo WK et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc.Natl Acad.Sci U.S.A 2002;99:8932-8937.

27

Study Proposal 1208-72 Study Title: Cellular Therapy Activity Survey in the US and Canada Marcelo Pasquini, MD, CIBMTR, Milwaukee, WI Helen Baldomero, MD, Basel Kantonsspital, Basel, Switzerland Objective:

1.1 Identify centers in the US and Canada with active cellular therapy programs and with ongoing clinical trials in regenerative medicine.

1.2 Assess current indications for cellular therapies for regenerative medicine in this region and cellular products utilized.

Scientific Justification: Treatment of diseases with cells has long been the hallmark of hematology practices with hematopoietic cell transplantation and transfusion medicine. Advancements in understanding of progenitor and stem cell biology in the bone marrow and other organs lead to initiation of a new field in medicine. The majority of these advancements are a natural evolution from hematopoietic cell transplantation. Graft manipulation in vivo and in vitro, from cell selection to genetically modified cells are done to improve transplant outcomes by reducing graft versus host disease, disease relapse or treat viral and fungal infections(1, 2). Further understanding of other bone marrow cells, the mesenchymal stromal cells and its protective relationship with immature hematopoietics cells lead to successful studies on treatment of graft versus host disease(3). Cellular therapies not only evolved in the HCT field but also beyond this field with application for treatment of cardiovascular, neurological, autoimmune diseases among other indications(2, 4, 5). These emerging indications for cellular therapy are expanding rapidly and published studies demonstrate a large variety of disease conditions and states, different cell types and different delivery routes. The heterogeneity in practices combine to an emerging field and limited number of patients makes comparisons and proper interpretation of results challenging. Furthermore, long term effects of these therapies, mainly using multipotent cells or cells infused after many passages, are still largely unknown. The CIBMTR and the EBMT(6) are in the process of developing cellular therapy registries, in order to capture this data to be studied in a systematic way in order to analyze cellular therapy outcomes for various indications. As the field expanded beyond HCT the transplant center network, the true activity of these treatments is not known. The EBMT developed a simple surveying tool to assess the activity in European countries. This tool captures annual activities of number of cellular therapies per indication and cellular product utilized. This proposal focus on application of the same survey on centers in the US and Canada, and on a subsequent phase expand it to other countries in the Americas. The result of this survey will not only help to understand the activity and indications for cellular therapies but to recognize centers with active programs, which would then be invited to participate in developing the cellular therapy registry.


28

Data Collection The survey will be distributed to all active transplant centers that contribute data to the CIBMTR. We recognize that not all centers will be performing cellular therapy and institutional programs for cellular therapies might not be associated with transplant programs. Thus we will need to expand this survey to other programs. We plan to discuss with different groups, such as the International Society for Cellular Therapy, American Society of Blood and Marrow Transplantation, American Association of Blood Banks, Specialized Centers for Cellular Therapy, Cardiac Cell Therapy Research Network, Product Assistant for Cellular Therapy among others in other to expand the number of survey recipients. A sample of the survey is included in figure 1. In additional to the survey sheet we will inquire whether CIBMTR affiliated institutions have ongoing cellular therapy programs and whether these programs are in any way associated with the HCT program, either by sharing personnel or facilities. The data will collected for one year of activity initially and depending on the results, this will be repeated annually for two additional years. Application of this survey will require IRB approval, which we plan if this proposal is approved to be done through the Medical College of Wisconsin. Methods: Once a list of centers and programs are recognized the survey will be sent. The results will be collated and summarized with descriptive statistics. The results will be them shared with the EBMT for a combined report of cellular therapy activity. References:

1. Ann M. Leen HEH. Cytotoxic T lymphocytes as immune-therapy in haematological practice. British Journal of Haematology. 2008;143(2):169-79.

2. Burt RK, Loh Y, Pearce W, Beohar N, Barr WG, Craig R, et al. Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. JAMA. 2008 Feb 27;299(8):925-36.

3. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. The Lancet.371(9624):1579-86.

4. Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, et al. Adult Bone Marrow-Derived Cells for Cardiac Repair: A Systematic Review and Meta-analysis. Arch Intern Med. 2007 May 28, 2007;167(10):989-97.

5. Jones KB, Seshadri T, Krantz R, Keating A, Ferguson PC. Cell-Based Therapies for Osteonecrosis of the Femoral Head. Biology of Blood and Marrow Transplantation. 2008;14(10):1081-7.

6. Le Blanc K, Fibbe W. A new cell therapy registry coordinated by the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2008 Feb;41(3):319.


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Figu

re 1

: Cel

lula

r The

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Sur

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not for publication or presentation · group that hematopoietic stem cell transplant (hct) was the...

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