**Executive Summary of the Tumor Immunology Think Tank**

Three major themes emerged from the presentations and discussions at the
Workshop:

**1) Unequivocal evidence has emerged from a number of sources of the
capacity of the immune system, alone and in combination with other
modalities, to effect clinically meaningful antitumor immune
responses**. Specific examples include: a) the growing success of
monoclonal antibody therapy (i.e., rituxan and herceptin), b) the
understanding that cure of leukemias and some lymphomas by allogeneic
BMT derives in large part from the antitumor response of donor T cells
transferred to the patient (the so-called graft-vs.-tumor effect). In
fact, GvT from donor lymphocytes is the only way to cure CML, c)
dramatic antitumor effects after adoptive transfer of melanoma-specific
T cells expanded [ex]{.underline} [vivo]{.underline}, d) antitumor
effects of IL-2 in melanoma and renal cell carcinoma.

**2) Recent advances in basic cellular and molecular immunology have
been truly revolutionary, and have given us an unprecedented framework
for understanding how the immune response is initiated and regulated,
from specific cell types (i.e., dendritic cells and T regulatory cells)
to specific molecules and signaling pathways**. An understanding of how
these pathways function and intersect, as well as how the immune system
naturally interacts with developing cancers, will provide unprecedented
insights and tools to effectively manipulate antitumor immunity.
Already, these insights are leading to the conclusion that [the most
effective immunotherapies will employ combinatorial approaches that
impact the antitumor immune response at multiple points]{.underline}.

**3) Infrastructure limitation with respect to preclinical models of
cancer, production of immune cells for adoptive therapy in patients,
vaccine generation and availability of clinical grade recombinant
molecules (i.e., cytokines, antibodies, etc.) for early phase clinical
testing are severely limiting progress in the translation of the most
promising immunotherapeutic combination strategies**. Additionally, the
growing regulatory burden for biologic therapies threatens to destroy
even the current ongoing progress toward clinical translation.

Facilitation of the development and translation of rationally designed
combination immunotherapy strategies should be the major NCI mandate in
this area. This will require the dual approaches of empowering
academically based groups for independent early stage translation as
well as proactive promotion of effective public-private partnerships in
this area.

**Introduction**

1)  **Enhanced understanding of immune regulation.**

It is becoming clear that the immune response is finely tuned via a set
of activation and inhibitory signals expressed by critical cellular
subsets. In addition to the continuously expanding knowledge base of T
cell and B cell biology, a new explosion of knowledge over the past
decade has occurred related to dendritic cells, NK cells, NKT cells and
T regulatory cells. Each of these cell types has been shown to be
central to regulation of both innate and adaptive immunity.

The myriad of cellular interactions that ultimately regulate immune
responses are mediated by specific ligand-receptor interactions that in
turn trigger intracellular signaling pathways. In addition to the
antigen receptors on T and B cells (TCR and BCR), over 100 cytokines and
cell surface molecules regulate the amplitude and quality of the output
response. These ligands and receptors, many of which have been
molecularly identified, appear to be roughly evenly divided between
activating (e.g., IFN-α,β,γ, Β7−1/2, CD28, CD40) and inhibitory (e.g.,
IL-10, TGF-β, CTLA-4, PD-1). Likewise, intracellular signaling pathways
triggered by receptors are becoming defined in terms of how they
activate or inhibit important immune effector functions as well as
cellular lifespan. Indeed, more than any other system in the body,
apoptosis control is a major mechanism of regulation in the immune
system.

a\) While much is known about individual molecules and pathways in
isolation, there is much more to be learned about how these pathways
interact in a coordinated fashion. [Understanding the physiology of
these interactions will require integration of classical molecular
biology and biochemistry approaches with newer approaches in 4 areas:
genomics, proteomics, systems biology and in vivo imaging]{.underline}.

b\) Enhancement of specific activation pathways or blockade of specific
inhibitory pathways has been shown to induce or exacerbate autoimmunity.
Conversely, early studies using antibodies and recombinant fusion
molecules has demonstrated that combinations of activating signals (such
as vaccines that enhance dendritic cell function) and blockade of
inhibitory signals (such as anti-CTLA-4) can dramatically enhance
antitumor immunity. [The development of combination approaches that
simultaneously activate tumor-specific or tumor-selective immunity and
block immunologic checkpoints is the most important translational
mission in the cancer immunology field]{.underline}. Maximizing the
window between antitumor efficacy and intolerable autoimmunity will
require a significant investment in understanding the mechanisms of
immune regulatory pathways.

2)  **Understanding the interaction between the immune system and the
    tumor microenvironment**.

It is now absolutely clear that tumors express tumor-specific (from
mutations and rearrangements), tumor-selective (gene expression changes
due to epigenetics), and tissue-specific antigens (relevant targets for
tumors derived from dispensable tissues) that the immune system can
potentially recognize. If the tumor were simply an inert bag of
antigens, the immune system would have no trouble eliminating all
cancers. However, tumors interact actively with their environment,
including the immune system. It is now emerging that an integral element
of tumor biology is the immunologic effects of oncogenic changes.
Examples include the inhibition of dendritic cell maturation by tumor
derived factors such as VEGF and the finding that activation or
inactivation of various Stat signaling pathways not only affect
tumorigenesis but also have profound effects on how the immune system
senses invading cancer cells. These interactions dramatically affect the
balance between immune surveillance and tolerance induction. At the
effector stage, it is clear that features of the tumor microenvironment,
such as stromal structure and hypoxia, dramatically affect the traffic
and function of immune effector cells at the metastatic site, even when
appropriately activated. [The mechanisms of immune interactions with the
tumor microenvironment is a critical and understudied area of cancer
immunology that will impact significantly on the success of
immunotherapy strategies. This is a specific area that the NCI should
encourage]{.underline}.

3)  **Infrastructure and regulatory barriers relevant to translation of
    promising immunotherapy combinations.**

The diversity of immune regulatory pathways amenable to manipulation
with vaccines, antibodies, and small molecule reagents offers both
unprecedented opportunities and challenges for effective translation.
Cell-based therapeutic opportunities, including adoptive T cell
approaches, dendritic cell vaccines and bone marrow transplant-related
immunotherapies, likewise offer tremendous opportunities and challenges.
[It is a general consensus that barriers to effective translation are
mounting rather than coming down. The realization of successful cancer
immunotherapy will live or die depending on whether translation is
facilitated or blocked]{.underline}. There were 4 areas that were
identified as critical to address:

a)  **Paucity of good preclinical mouse cancer models useful in
    immunological studies**. Cancer immunology was largely ignored in
    the animal models consortium efforts despite the fact that some of
    the most important innovations in mouse genetics were pioneered to
    study the immune system in vivo. A specific effort to make the
    opportunities and resources of the animal model consortium directly
    available to the cancer immunology field is important. This will
    require a proactive effort on the part of the NCI.

b)  **Measurements of human immune responses**. Although anti-tumor
    responses are the final arbiters in the evaluation of tumor
    immunotherapies, development of these therapies will only proceed in
    an efficient and rational manner if better means of measuring human
    immune responses are developed. Current methods are largely
    [ex]{.underline} [vivo]{.underline} and do not necessarily inform us
    about the behavior of the cells or agents in the patient.
    Substantial opportunities exist for NCI to actively promote the
    development of novel methods for the detection and measurement of
    the activity of the human immune system. Specific attention should
    be given to non-invasive imaging methods, including but not limited
    to PET and MRI based methods. These approaches can be used not only
    with labeled cells to evaluate homing to tumor sites, but also
    potentially for high-resolution determination of [in]{.underline}
    [situ]{.underline} lymphocyte function such as cytokine secretion or
    cytotoxic granule release.

c)  **Lack of availability of clinical grade biologic reagents to the
    immunotherapy community**. As described above, there is a wealth of
    exciting biologic reagents that, if applied in proper combinations,
    can dramatically enhance immunotherapy potency. These range from
    antibodies (i.e., anti-CTLA-4), soluble ligands (i.e., soluble
    CD40L), and cytokines (i.e., IL7, flt-3L) to more complex
    recombinant viral and bacterial vaccines and finally engineered
    cells. Most of these are virtually unavailable to the immunotherapy
    community.

> The three current sources for production of these reagents are
> invaluable, but at present not adequate to meet the increasing need.

i)  [RAID]{.underline} -- while BRB/RAID is a critical mechanism to
    produce biologic reagents for investigators and has an extremely
    dedicated and expert development staff, its ability to supply these
    reagents is far too slow. Only a tiny fraction of RAID-approved
    reagents have been delivered and most that have been delivered take
    \>3 yrs to produce. These delays are due to understaffing (staff is
    \<10% required to complete the project portfolio relative to
    industry standards), tremendous bureaucratic inefficiency, lack of
    appropriate expertise among the review groups that select projects
    into the pipeline (gumming the system with flawed projects), and
    ineffective outsourcing and backsourcing.

ii) [Institutional Processing Facilities]{.underline} -- These
    facilities are becoming an important resource for institutions with
    highly active translational missions. However, they are extremely
    expensive to maintain. None of the NCI funding sources come close to
    adequately supporting these facilities.

iii) [Companies]{.underline} -- Biotechnology and pharmaceutical
     companies own a tremendous number of valuable molecules and more
     complex reagents at the level of patents, production expertise and
     actual clinical grade stocks. Most of these reagents are not
     available to the immunotherapy community to use in novel and
     promising combinations and many are not being developed at all.
     Much of this problem comes from the corporate culture of favoring
     complete control over the reagent over release of the reagent to
     groups that wish to utilize it in a fashion other than what the
     company is interested in or in combination with agents not owned by
     the company.

**d) Regulatory barriers.** FDA barriers continue to mount, driving the
cost and administrative burden of doing the most innovative trials to
virtually unbearable levels. The burdens are typically borne by the
translational clinical investigator, who has minimal resources to meet
the requirements. Some of the problem is that communication between FDA
and investigators is inadequate. Much of the problem is that the NCI and
the immunotherapy leadership are not appropriately educating the FDA on
which safety regulations are necessary vs. frivolous, relative to the
severity of the disease being treated.

**Specific Recommendations for the NCI:**

1)  Continue to promote basic research on mechanisms of immune
    regulation with special emphasis on interactions between immunology
    and tumor biology/microenvironment. This could involve an RFA to
    bring together tumor biologists and immunologists to specifically
    address these questions. In addition, promote the development of
    animal models of cancer useful for the testing of immunotherapies.

2)  Promote the development and application of new imaging technologies
    to study immune function [in]{.underline} [vivo]{.underline} in both
    animals and patients.

3)  Create a mechanism for supporting collaborative, interdisciplinary
    consortia that is not organ site focused but rather modality focused
    -- i.e. immunotherapy. This would greatly facilitate interactions
    among immunologists, cancer biologists, and clinical investigators
    interested in translating the most innovative and promising
    combination immunotherapy approaches. Inter-institutional
    collaborations should be emphasized with this mechanism. To provide
    optimal flexibility as well as emphasis on translational work, this
    mechanism could be based in part on the SPORE model.

4)  Develop a strategic plan to effectively identify, acquire, and make
    available to the community the most promising immunomodulatory
    reagents such that their creative clinical development is most
    efficiently facilitated. This will involve a paradigm for
    interaction with the corporate world as part of the "public-private
    partnership".

5)  Improve the availability of new biologics for immunotherapy by:

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a)  Convening a blue ribbon panel to review BRB/RAID that will be
    charged with developing specific recommendations on how to enhance
    the efficiency, quality and speed of reagent production.

b)  Developing a mechanism to support infrastructure for the most active
    institutionally based facilities committed to cellular and biologic
    reagent production for biologic therapy of cancer.

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6)  Develop a strategic plan to proactively interface with the FDA so
    that regulations are applied intelligently and flexibly and
    communicated in an effective and consistent fashion to clinical
    investigators. This should involve the recommendation of a separate
    review process for academically based pilot trials of combination
    immunotherapy approaches for patients with advanced cancer or those
    prognostically defined as a high probability of relapse. Also,
    because of the unique regulatory issues associated with biologic
    reagents as opposed to small molecules, consideration should be
    given to creating an NCI advisory/liaison group to the FDA biologics
    branch.