CENTER OF EXCELLENCE IN IMMUNOLOGY

STEERING COMMITTEE MEETING

SUMMARY MINUTES

September 15, 2008

# CENTER OF EXCELLENCE IN IMMUNOLOGY

**STEERING COMMITTEE MEETING**

September 15 2008

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

**Bldg. 31, Room 3A11**

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

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

**Overview**

The Center of Excellence in Immunology Steering Committee (CEI SC)
convened its monthly meeting on September 15, 2008, in Building 31, Room
3A11 with videoconference available in Building 549, Conference Room A,
Frederick. Dr. Robert Wiltrout called the meeting to order at 1:00 p.m.
Dr. Rosenberg presented a summary of the Cancer Immunology and
Immunotherapy Meeting. Dr. Crystal Mackall presented a summary of the
Pediatric Immunotherapy Meeting. Dr. Howard Streicher presented an
update on the status of clinical grade IL-12.

**Summary of the Cancer Immunology and Immunotherapy Meeting -- Dr.
Steven Rosenberg**

Dr. Rosenberg gave a summary of the meeting "Cancer Immunology and
Immunotherapy: Realizing the Promise" conducted on September 11 &12,
2008 in Masur auditorium with overflow seating in Lipsett auditorium.
The meeting was well attended with over 600 scientists. Another meeting
with the theme of immunology and immunotherapy will likely be conducted
every 2 or 3 years. Members agreed that basic immunology and molecular
immunology should also be covered in future meetings.

**Summary of the Pediatric Immunotherapy Meeting -- Dr. Crystal
Mackall**

Dr. Mackall gave a summary of the Pediatric Immunotherapy Meeting
conducted on September 9 & 10, 2008 at the Cloister Center. The meeting
was a small pediatric oncology community meeting and was well attended
with about 80 scientists. Attendees of the meeting felt that a similar
meeting should be held every 18 months or so.

**Update on the status of clinical grade IL-12 -- Dr. Howard Streicher**

Dr. Streicher presented a summary of the status of clinical grade IL-12.
In spite of the fact that IL-12 has been in clinical trials from the
mid-1990s, clinical studies have been disappointing, both for infectious
diseases and cancer, either as a single agent or in combination with
other agents. Biologic activity is thought to be mostly through the
induction of interferon gamma, and can lead to severe toxicity including
fatigue, hypotension, hepatic failure, anemia, and GI bleeding. There is
limited information regarding progression-free or overall survival but
no clear immunologic marker to guide development has been identified.
IL-12 was withdrawn by the manufacturer Wyeth in 2006. CTEP-sponsored
studies were closed in January 2006. DCTD recently had a gift from Wyeth
of 10,000 recovered 50ug single use vials (roughly the equivalent of
10,000 adult doses), which DTP can use without restrictions. There will
be no additional material without new manufacture by NCI. These were
donated by Wyeth Inc. to DCTD and re-certified by DTP at FCRC. CTEP is
working on the details of a solicitation so the material will be
available to investigators.

Dr. Streicher presented an overview of clinical data on IL-12 obtained
from publications, investigator brochures, and from talking to
investigators. There were a variety of clinical studies done by Wyeth as
well as under a Hoffmann La Roche program. The NCI sponsored 18 trials
that included \~800 patients. There were 29 CR and 76 PR responses, most
of them (20 CR, 36 PR) in 2 studies, one on Kaposi Sarcoma and another
in Non-Hodgkin's Lymphoma. rhIL-12 was strongly recommended by the
Immunotherapy Working Group Workshop for development as a vaccine
adjuvant. For example, in pre-clinical studies, P1A peptide-pulsed PBMC
with IL-12 showed significant increase in percent specific lysis
compared with PBMC plus IL-12 or PBMC-P1A alone. In a related clinical
study of immunization with melanoma peptide-pulsed PBMC with IL-12,
T-cell responses were seen with clinical responses in two patients
(10%). Another study showed that alum with IL-12 augments immunity to a
melanoma peptide vaccine and augments TH1 responses in vitro. However,
the effects were not encouraging in three separate studies with
pneumococcal vaccine, hepatitis A vaccine, and influenza vaccine.

A 300--500 ng/kg biw sc dose of IL-12 has had activity limited to
AIDS-related KS and CTCL. Combinations of IL-12 with IFN-alpha or
antibodies (herceptin, rituximab) showed little if any clinical
activity. While there is strong evidence for biologic activity in the
stimulation of IFN-gamma, this is accompanied by rapid tachyphylaxis.
IFN responses may be restored with IL-2, but the mechanism is uncertain.
There is limited evidence that IL-12 stimulation of IFN-gamma and
downstream IFN gene targets such as IP-10 have been able to mediate
clinical responses even when there is sustained induction of IFN-gamma.
Recombinant human IL-12 given systemically as a single agent has limited
therapeutic activity which may be the result of toxicity, tachyphylaxis,
or the loss of responses to IL-12-induced interferons.

Some possible circumstances where IL-12 may be clinically useful
include: local or intra-tumoral administration; as an adjuvant as
opposed to systemic administration; in combination with TLR stimulation,
CD40 antibody, and lenalidomide; addition of class II epitopes or
carriers such as the Mage 3 ASO2B combination; dendritic cell
vaccination with *ex vivo* stimulation; adoptive T-cell transfer. Some
suggestions for enhancing IL-12/IFN effects include: combination with
IL-2 to maintain IFN-IP10 pathway; reversal of IFN pathway
non-responsiveness by decitabine; immunologic stimulation or removing
restraints (e.g., anti-CTLA-4, chemotherapy, anti TGF-beta, 4-1BB,
anti-PD-1, lenalidomide); antiangiogenesis to augment IP-10 (e.g.,
Avastin, axitinib/sunitinib, VEGF-trap). Further combination studies
with IL-2 may be of interest, however investigators may not want to
include patients who have been treated with IL-2 but did not respond.

A solicitation is being prepared that will invite proposals further
investigating the possible clinical usefulness of IL-12. Of the 10,000
vials available, 2000 vials were allotted for three studies that have
been reopened. These are: (i) a phase 1 study on IL-12/IL-2 combination
in renal carcinoma, (ii) a phase 1/2 study in pediatric neuroblastoma,
and (iii) a phase 2 study of a dendritic cell fusion vaccine in breast
cancer. Other areas of interest are vaccine adjuvant studies, possible
studies by immune network, and other proposals based on LOIs. About 4000
vials may be set aside for these areas. The rest of the vials may be
used for studies on systemic therapies, anti-angiogenesis, and any other
high priority areas at the Clinical Center.

Dr. Restifo briefly described his studies on IL-12 in mice, including:
monotherapy studies where the results were not encouraging; in
conjunction with vaccine both as recombinant protein and as recombinant
protein encoded in vaccinia virus, both alone and in combination with
co-stimulatory molecules and antigen. Only small nonvascularized tumors
were treatable for three or four days. Large established tumors were
also treated using adoptive immunotherapy by polarizing CD8 cells.
However there are a number of problems to translate these findings into
patients, mainly because IL-12 may limit the proliferation of CD8 cells.
However, his studies do indicate that IL-12 is useful as a culture
agent. In vivo, IL-12 in combination with adoptively transferred cells
is promising. Adoptive transfer into a large established tumor even in
the absence of vaccination could lead to augmentation of function.
Therefore, IL-12 could have a role in adoptive immunotherapy but some
more studies may be needed before the findings can be extended to
patients.

The committee acknowledged that there is a conceptual interest in IL-12
and may consider sponsoring a meeting on IL-12 in the future.

The meeting adjourned at 2:30 p.m.

**Next Meeting: October 20, 2008, 1:00--3:00 p.m.**

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

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