Immunotherapies: Great Therapeutic Potential in Oncology

Among the conclusions reached by participants in the Tumor Immunology Think Tank sponsored by the Division of Cancer Biology of the U.S. National Cancer Institute and charged with recommending to NCI a research agenda that would accelerate cancer research, was the clear importance of immunotherapies in the development of treatment approaches in oncology (Think Tank co-organizers: James P. Allison, Ph.D., Howard Hughes Medical Institute, University of California Berkeley; Drew Pardoll, MD., Ph.D., Professor, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore; January 22-24, 2003).

As reflected in the NCI Executive Summary of the Think Tank recommendations, 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.

In addition, 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. The Workshop participants concluded that 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.

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.

Challenges

Current chemotherapies are becoming more and more potent and selective; in fact, the combined use of chemotherapies has allowed significant clinical progress in cancer treatment and disease outcomes
Of particular note are recent breakthroughs based on innovative approaches utilizing kinase inhibitors for inhibition of intracellular signaling and the use of monoclonal antibodies for inhibition of angiogenesis
Nevertheless, chemotherapies often fail at eliminating residual disease, the main source of relapse
Thus, residual disease is an ideal target for immunotherapy because the tumor burden is limited and accessible to T cell effects
Recent but complex approaches, such as those developed by Steven A. Rosenberg, MD, Ph.D., Chief of Surgery at NCI (Powell DJ et al J Immunol. 2006 Nov 1;177(9):6527-39; Morgan RA et al Science. 2006 Oct 6;314(5796):126-9) and Carl H. June, MD, Director of Translational Research at the Abramson Cancer Center of the University of Pennsylvania, (Rapoport AP et al Nat Med. 2005 Nov;11(11):1230-7) have demonstrated the great potential of immunotherapies in small Proof of Concept studies
Additionally, various large cancer vaccine trials (Harsztak AL and Small EJ, Expert Opin Biol Ther. 2007 Dec; 7(8):1275-1280) are ongoing and should provide further evidence of the potential of immunotherapeutic approaches.

Limitations of Current Immunotherapies in Oncology

Most cancer patients suffer from varying degrees of immunodepression
Current immunotherapies do not stimulate the production of sufficient numbers of active T cells to generate an effective anti-tumor response
While these current therapies do stimulate production of some specific T cells, these are often short lived and prone to apoptosis
Importantly, these therapies do not stimulate the production of new T cells or a broad T cell repertoire; nor do they provide long term protection through the emergence of central memory pools
Thus, these T cells are quickly anergized by tumors and associated multifunctional peptides such as TGF-β, that controls proliferation, differentiation, and other functions, including apoptosis, in many cell types

The pre-clinical models developed by Cytheris together with the company’s recent Phase I studies of IL-7 suggest that this cytokine could play a critical role in overcoming the limitations of current immunotherapies in oncology.

Cytheris preclinical models and two Phase I studies in oncology demonstrate that:

IL-7 treatment stimulates production of significant numbers of T cells, both CD4 and CD8, and makes them available to produce anti-tumor-specific responses
The IL-7 anti-apoptotic effect (as measured by Bcl-2) – results in long lived T cells
The IL-7 thymopoietic effects -- produce Recent Thymic Emigrants, naïve T cells and contribute to repertoire broadening
The IL-7 co-stimulating effect -- also broadens the response repertoire to sub-dominant epitopes
IL-7 antagonizes both the production and signaling of TGF-β and as such limits the production of suppressor T regs as well as T cell anergy/exhaustion
IL-7 supports the production of long lived central memory T cells

All these clinical effects were observed at dose levels compatible with good clinical tolerance; in particular IL-7 does not induce any “cytokine storm syndrome.

Current Cytheris Clinical Studies with IL-7

Glycosylated IL-7 is currently being studied in a large Phase I study at the U.S. National Cancer Institute (Steven A. Rosenberg, MD, Ph.D., Principal Investigator) to determine tolerance and immune activity in both lympho repleted and lymphopenic patients
A second study, initiated at Memorial Sloan-Kettering Cancer Center, New York, (Marcel van den Brink, MD, Ph.D., Principal Investigator) is designed to show the immune reconstitution effects of IL-7 following T cell depleted allograft

Delayed and deficient reconstitution of T cell populations and their functions constitute a major obstacle to the success of a hematopoietic stem cell allograft. Experimental studies demonstrate that IL-7 can promote recovery of thymopoiesis, peripheral lymphoid populations and their functions in murine recipients of allogeneic hematopoietic stem cell transplantation (HSCT) without augmenting Graft versus Host Disease (GVHD).

How Cytheris plans to develop pragmatic approaches to demonstrate the clinical potential of IL-7:

The combination of IL-7 with another cytokine, such as IL-2 or Interferon could produce a set of potent combined effects for treatment of some of the most immune sensitive tumors, such as melanoma or renal cell carcinoma.
One of the most obvious development avenues would be the combination of IL-7 with a therapeutic cancer vaccine to improve the basic activity detected with the vaccine. In this model, IL-7 pre-treatment prior to introduction of the vaccine should provide significant benefit by inducing the production of a large number of good and long lived T cells in support of the anti-tumor specific response stimulated by the vaccine. This very simple, pragmatic and conventional approach could target large numbers of patients and various cancers at the stage of residual disease, when tumor cells are easily accessible to immunotherapies. Positive results in a pre-clinical model with two Cell Genesys cancer vaccines support this approach (Li B et al, Clin Immunol. 2007 May; 123(2):155-65).
Another promising approach is suggested by recent discoveries based on immune analysis of classic chemotherapies: during chemotherapy, tumor lysis releases two classes of molecules which provide a favorable environment for triggering an immune response:

various self antigens, specific to patient tumors;
the intra-cellular high-mobility-group box 1 (HMGB1) alarmin protein, now identified as a very potent antigen presenting cell activator. In fact during chemotherapy or radiotherapy, dying tumor cells secrete HMGB1 which by interacting with Toll-like receptor 4 (TLR4) stimulates dendritic cells (DCs) to cross-present antigens from the dying tumor cells.

This recently discovered process remains ineffective in most patients undergoing chemotherapy because most such treatments are immune-suppressive to different degrees. Nevertheless this mechanism is effective since patients with a non-mutated TLR4 allele have a much better prognosis after breast cancer treatment with anthracyclins than those carrying a TLR4 loss-of-function allele. These results clearly indicate a clinically relevant immunoadjuvant pathway triggered by tumor cell death (Apetoh L et al, Nat Med. 2007 Sep; 13(9):1050-9).

These discoveries were discussed at the mini-symposium entitled“Interleukin-7 in Health and Disease” in the series ‘Frontiers in Medicine’ at the Nobel Forum, Karolinska Institutet, held in Stockholm, Sweden, September 17–18, 2007, and encouraged Cytheris to consider an “IL-7 add-on therapy” which, when combined with classical chemotherapeutic approaches, could facilitate the triggering of a potent and broad immune response against tumor antigens. The Company believes this “IL-7 add-on therapy” will be relatively easy to implement, with biomarkers such as circulating tumor cells utilized to quickly indicate the benefit of this treatment.

In summary, IL-7’s pleitotropic set of immune activities could unlock the considerable potential of various immunotherapies in oncology, including the recently identified immune therapeutic activity of some chemotherapies. The development of this clinical approach could be easily developed as an “add-on therapy” without requiring complex cellular treatment and manipulation. This approach could address many cancers, including those with the highest incidence such as breast, prostate and colon carcinomas.