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 vivo, 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.

 

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-a,b,g, B7-1/2, CD28, CD40) and inhibitory (e.g., IL-10, TGF-b, 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.

           

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. 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.

 

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.  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 vivo 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 situ 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 – 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 – 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 – 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 vivo 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:

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.

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.