CENTER OF EXCELLENCE IN IMMUNOLOGY

STEERING COMMITTEE MEETING

SUMMARY MINUTES

November 19, 2007

# CENTER OF EXCELLENCE IN IMMUNOLOGY

**STEERING COMMITTEE MEETING**

November 19, 2007

1:00--3:00 p.m.

**Bldg. 31, Room 3A11**

**Videoconference to Frederick, Bldg. 549, Conference Room B**

> **Members present:** Dr. Robert Wiltrout *(Chair)*
>
> Dr. Jonathan Ashwell
>
> Dr. Allan Hildesheim
>
> Dr. Diana Linnekin
>
> Dr. Crystal Mackall
>
> Ms. Karen Maurey *(Adjunct)*
>
> Dr. Joost Oppenheim
>
> Dr. Ira Pastan
>
> Dr. Marjorie Robert-Guroff
>
> Dr. Steven Rosenberg
>
> Dr. Jeffrey Schlom
>
> Dr. Giorgio Trinchieri
>
> Dr. Thomas Waldmann
>
> Dr. Howard Young
>
> **Members absent:**
>
> Dr. Jay Berzofsky
>
> Dr. Stephen Creekmore *(Adjunct)*
>
> Dr. Ronald Gress
>
> Dr. Jeffrey Lifson
>
> Dr. Douglas Lowy
>
> Dr. Alfred Singer
>
> Dr. Dinah Singer
>
> Dr. Robert Yarchoan
>
> **Guests:** Dr. Rao Bachoti
>
> Mr. Ray Butler
>
> Dr. Laura Hooper

######### Handouts

1.  Agenda

2.  Handouts by Dr. Waldmann

**Overview**

The Center of Excellence in Immunology Steering Committee (CEI SC)
convened its monthly meeting on November 19, 2007, in Building 31, Room
3A11 with videoconference available in Building 549, Conference Room B,
Frederick. Dr. Robert Wiltrout called the meeting to order at 1:10 p.m.
Dr. Wiltrout mentioned that the President vetoed the Department of
Health and Human Services budget and that we will operate on a
continuing resolution until a budget is approved. Dr. Waldmann provided
an update on the IL-15 production and progress toward the Phase I trial.
Dr. Giorgio Trinchieri provided an update on the Trans-NIH initiative
for the *Center for Immunology, Autoimmunity, and Inflammation*. Dr.
Rosenberg provided an update on the 2008 Meeting on *Cancer Immunology
and Immunotherapy.*

**Update on the IL-15 production and progress toward Phase I trial --
Dr. Thomas Waldmann**

Dr. Waldmann provided an update on the availability and production
status of IL-15, planned toxicology studies, and pre-IND submission for
a proposed clinical trial.

About 300--400 mg of pure IL-15 has been prepared by the
Biopharmaceutical Development Program (BDP) and is available for animal
studies. Toxicology studies will be initiated by January 2008. It is
estimated that vialed material for clinical trial will be available by
August 2008.

A pre-IND package was submitted to the FDA detailing the proposed
clinical trial, toxicology studies, the validated tests for the
measurement of IL-15 for pharmacokinetic studies, use of IL-15
antibodies, as well as ex vivo growth of T-cells. The FDA has agreed to
a conference call to discuss the proposal on November 30, 2008. The
discussions will include representatives from the FDA, the BDP, and the
CCR. The use of IL-15 in HIV/AIDS was not included in the pre-IND
package in order to remain focused and simplify the FDA approval
process. Two issues discussed at the CEI SC meeting were 1) toxicology
analysis, and 2) administration of multiple doses as opposed to a single
dose. The proposed study is a GLP toxicology analysis. Others have
conducted non-GLP analyses administering multiple doses that included
high doses of IL-15 in Rhesus macaques. The only toxicity observed was a
change in platelet count. There were no capillary leaks, no pathology,
and no immunologic toxicity except for a vaccine-like response resulting
in increase in CD8^+^ cells and NK cells after testing an
immunologically active dose. The doses tested were 25--100 µg/kg, so the
doses envisioned for humans are 3--25 µg/kg. The dosing proposed for
Rhesus is administration of one dose per day by infusion for 12 days for
a total of 12 doses.

The IL-15 to be used in the proposed studies is produced using an *E.
coli* expression system. Two antibody assays will be used to assess
immunogenicity -- ­a sensitive two-arm capture quantitative ELISA assay
and a functional CTIL-2 proliferation bioassay that measures the
inhibition of IL-15 by the produced antibody. NIAID is interested in
funding the production of mammalian IL-15 as backup and will make it
accessible to the NCI researchers. Some members of the CEI SC felt that
NCI may want to consider producing mammalian IL-15 since that will
likely be less immunogenic than *E. coli* IL-15.

The CEI SC expressed hope that the FDA will not require the NCI to
administer a single dose per patient. It was mentioned IL-7 was given in
3--6 doses. If multiple dose schedules are approved, the protocol will
be submitted to PRMC and IRB for approval.

In summary, the NCI currently has 300--400 mg of IL-15 which is not
officially GMP quality but prepared according to GMP procedures and
guidelines. It is estimated that 200 mg of this material will be needed
for toxicology studies. Dr. Wiltrout mentioned that if researchers from
NCI or NIAID would like small amounts of purified IL-15 for in vitro
studies, they may submit a short proposal stating the amount needed and
the plan of study. The request will be reviewed by the CEI SC.

Dr. Waldmann mentioned that the recent NCI Immunotherapy Agent Workshop
listed over 20 immunotherapy agents desired by the scientific community
and ranked these according to need. IL-15 was described as the most
desired agent and anti-PD1, IL-12, and anti-CD40 were the 2^nd^, 3^rd^,
and 4^th^ in order of importance. Dr. Waldmann described mouse
experiments in which combination therapy of a low dose of mammalian
IL-15 and anti-CD40 resulted in significant increase in survival of mice
injected with CT26 colon carcinoma tumor cells compared with
administration of either agent alone. He advocated that the availability
of both agents to researchers is highly desirable and their combined use
will be efficacious and cost-effective at the same time.

**Update on the Trans-NIH inflammation initiative -- Dr. Giorgio
Trinchieri**

Dr. Trinchieri provided an update on the proposed NIH Center for Human
Immunology, Autoimmunity, and Inflammation. He provided a brief history
of the initiative, as well as summarized discussions from a series of
recent meetings that explored the possibilities for funding and creating
space for the new Center.

Dr. Trinchieri elaborated on the justification, scope and goals of this
initiative. Many common diseases share immunologic/inflammatory
pathophysiologies but have not been studied in a coordinated way. New
technologies like genomic science are driven by large multidisciplinary
projects which are difficult to be handled by individual laboratories.
NIH has world-class immunology expertise and could benefit from a
concerted immunology program that spans all the Institutes. The Center
will strive to coordinate the various studies in immunology and position
the NIH to become the leading institution in human immunological
research. If the initiative comes to fruition, there will be a targeted
and integrated clinical, epidemiologic, basic, and educational approach
with a bench-to-bedside bidirectional translational program. The Center
would be physically located within or close to the Clinical Center to
facilitate close interaction among scientists.

One example of a possible initial project for the Center deals with
unifying research across the NIH on Tumor Necrosis Factor (TNF). TNF is
involved in numerous diseases and is being investigated in eleven
clinical trials at six NIH Institutes. These studies could all
potentially benefit from an organization facilitating interaction and
integration of efforts among all the scientists involved in these
studies.

The CEI SC questioned whether the new Center would be a new Laboratory
or a Branch. Dr. Trinchieri clarified that the present plan is for a
physical structure with a budget of \$65 millions in five years and
total of 70--120 people, half of them full time investigators and the
other half collaborating/rotating intramural scientists. There would
also be a technological core and a clinical protocol support group.

Another question raised by the CEI SC is who will treat patients
enrolled in the Center's clinical trials? Dr. Trinchieri clarified that
the Center will have clinical staff to take care of the patients. The
Center is envisioned as a resource for intramural scientists across the
NIH, not a replacement for existing Institutes. A major concern
expressed by the committee was whether substantial funds will be
diverted from CCR for building the new Center. The Committee hopes that
additional funds will be obtained to finance this effort.

The next planned step is a meeting of the NIH Centers' Scientific
Directors with the NIH Director Dr. Elias A. Zerhouni to discuss the
planning and the implementation of the three Intramural Trans-NIH
initiatives..

**Update on the 2008 Immunotherapy Meeting -- Dr. Steven Rosenberg**

Dr. Rosenberg gave an update on the preparations for the 2008
Immunotherapy Meeting. Masur Auditorium and Lipsett Auditorium are
reserved for September 11 &12, 2008. An important goal is that all
interested scientists will be able to attend. Dr. Rosenberg is in the
process of forming a Program Committee and suggested the title, "Cancer
Immunotherapy: Realizing the Promise". Areas of interest for the meeting
would be immunologic approaches that can improve the management of
cancer patients, e.g., regression of disease, prevention of disease,
recurrence, etc. As in previous meetings, speakers will be from both the
intramural and extramural communities. .

Dr. Diana Linnekin briefly discussed methods of advertising the meeting
to the extramural community.

The meeting adjourned at 3:00 p.m.

**Next Meeting: January 28, 2007**

**Location: Building 31/Room 3A11**

**Videoconference to Frederick: Building 549 Conference Room A**