Last year I Blogged about the Missing Link in T-cell activation with a vaccine. We were missing the Proflammatory Cytokines that produce the "Danger Signal" to the Immune system. Well Dr. Gajewski has come out and has backed up my theory.
Along with that, there are Two companies that are persuing this theory with Cytokine Therapy.
Thomas F. Gajewski, MD, PhD (University of Chicago) presented on the key role that the tumor microenvironment plays in determining the outcome of a tumor immune response. He noted the complexity of the tumor with respect to its structural and cellular composition and that the functional phenotypes of these cells may or may not permit an effective anti-tumor response at either the priming or effector phase. Characteristics of the tumor microenvironment may dominate during the effector phase of an anti-tumor T cell response, limiting the efficacy of current immunotherapies by inhibiting T cell trafficking into the tumor, eliciting immune suppressive mechanisms within the tumor, altering tumor cell biology and susceptibility to immune-mediated killing, or modifying the tumor stroma (i.e., vasculature, fibrosis). These features can be interrogated through pre-treatment gene expression profiling of the tumor site in individual patients; such an analysis may identify a predictive biomarker profile associated with clinical response. This strategy may also help identify biologic barriers that need to be overcome to optimize therapeutic efficacy of vaccines and other cancer immunotherapies. Mouse models have helped to define the hallmarks of an anti-tumor response, taking into account the effector phase within the tumor microenvironment. Based on these models, a DC subset (CD8α+) appears necessary for priming of host CD8+ T cells through cross-presentation of antigen within the draining lymph node. Antigen specific naïve CD8+ T cells that recognize the antigen within the lymph node and receive appropriate co-stimulatory and proliferative signals acquire their effector phenotype. In order to assert immune control over the tumor, these effector CD8+ T cells must enter the bloodstream, and via chemokine signals, traffic to the tumor site; once there, these T cells must overcome immune regulatory/suppressive mechanisms. In a small study of an IL-12-based melanoma vaccine, Dr. Gajewski and colleagues correlated pre-treatment biopsy gene expression to outcomes and noted that in responding patients, tumors expressed chemokines (e.g., CXCL9 which binds CXCR3 on activated CD8+ T cells), which in some instances were able to recruit T cells into the tumor site. A broader transcript analysis of banked melanoma tissue demonstrated a subset of tumors with T cell markers co-associated with a panel of chemokines. Among responders in the vaccine trial, there was a pattern of expression of T cell- recruiting chemokines, T cell markers, innate immune genes, and type I IFN—all of which indicate productive inflammation. These results were supported by other cancer vaccine studies that demonstrated a strong correlation between survival and the expression of T cell markers and chemokines within the tumors. The results from these gene expression studies may be useful in identifying biomarkers that could provide valuable information for selecting patients most likely to respond to immunotherapies. Additionally, these studies point toward specific strategies for overcoming immunologic barriers to immunotherapy at the level of the tumor microenvironment. Thus,
based on gene expression profiling, tumors can be categorized as T cell poor tumors, which lack chemokines for recruitment and have few indicators of inflammation, and T cell rich tumors, which express T cell recruiting chemokines, contain CD8+ T cells in the tumor microenvironment, and have a broad inflammatory signature. A strong presence of T cells within the tumor is predictive of clinical benefit from vaccines.
These observations prompt several important questions: 1) What dictates recruitment of activated CD8+ T cells into the tumor?
2) Why are tumors with CD8+ T cells not spontaneously rejected?
3) What are the innate immune mechanisms that promote spontaneous T cell priming in a subset of patients?
4) What oncogenic pathways in tumor cells drive these two distinct phenotypes?
Studies of CD8+ T cell recruitment to the tumor site point to a panel of chemokines, all of which may be produced by the melanoma tumor cells themselves. These studies suggest potential strategies to promote effector T cell migration to the tumor site that may include: direct introduction of chemokines; direct induction of chemokine production from stromal cells; eliciting local inflammation that generates chemokines (e.g., via type I IFNs, TLR agonists and possibly radiation); and altering signaling pathways in melanoma cells to enable chemokines expression by the tumor cells. Studies that have been designed to evaluate why melanomas that attract CD8+ T cells are not spontaneously rejected have pointed to several mechanisms that may exert negative regulation of T cells within the tumor microenvironment, including T cell inhibition via IDO and PD-L1, extrinsic suppression via CD4+CD25+FoxP3+ Tregs, and T cell anergy due to deficiency of B7 costimulation in the tumor microenvironment. Dr. Gajewski presented data that indicate that the immune inhibitory mechanisms present in the melanoma tumor microenvironment are driven by the CD8+ T cells, not the tumor. For example, IFNγ is the major mediator for IDO and PD-L1; and CCL22 production by CD8+ T cells is the major mediator for Tregs. Thus, blockade of these mechanisms may represent attractive strategies to restore anti-tumor T cell function and promote tumor rejection in patients.
To address questions underlying the mechanisms that promote spontaneous T cell priming in a subset of melanoma patients, Dr. Gajewski and colleagues used gene array data to identify markers of innate immunity that correlated with T cell infiltration. Melanoma metastases that contained T cell transcripts also contained transcripts known to be induced by type I IFNs. A knock-out mouse model demonstrated the necessity of the type I IFN axis for effective priming of a spontaneous T cell response and tumor rejection. Additional studies in knock-out mice have demonstrated that the CD8α+ DC subset is responsible for this spontaneous T cell priming. In an effective anti-tumor response sensing of the tumor by a separate DC subset drives type I IFN production, which is required for CD8α+ DC cross-priming of T cells. This suggests additional pathways that could be altered to promote spontaneous priming and an effective tumor response (e.g., provision of exogenous IFNβ). In summary, there is heterogeneity in patient outcomes to cancer immunotherapies (e.g., melanoma vaccines). One component of that heterogeneity is derived from differences at the level of the tumor microenvironment. Key factors in the melanoma microenvironment include
chemokine-mediated recruitment of effector CD8+ T cells, local immune suppressive mechanisms, and type I IFNs/innate immunity. Understanding these aspects should improve patient selection for treatment with immunotherapies (predictive biomarker), as well as aid the development of new interventions to modify the microenvironment to better support T cell-mediated rejection of tumors.
Source: http://www.translational-medicine.com/content/pdf/1479-5876-9-18.pdf
Induction of an immune response by antigen vaccination. Active immunization occurs following administration of tumor antigens, which are processed by antigen-presenting cells resulting in activation of immune effector cells such as T lymphocytes and B lymphocytes. Effector cells fight the tumor through several different effector pathways such as antibodies, cytokines or direct cellular interaction (Fas/Fas ligand, perforin/granzymes). Ideally this results in immunologic memory with long-lasting immunity against the tumor. Stimulation of the innate immune system is also known to have an important role in the evolution of an adaptive immune response (e.g. a rapid burst of inflammatory cytokines leads to activation of DC and macrophages). However, tumor-specific T cells also secrete chemokines (e.g. RANTES, MIP-1) that attract cells of the innate immune system to the tumor site. This mechanism may further contribute to the tumoricidal activitiy exhibited during T cell-mediated tumor regression. (TCR: T cell receptor, MHC: major histocompatibility complex, DC: dendritic cell, PMN: polymorphonuclear neutrophil, NK: natural killer cell, NKT: NK T cell, RANTES: regulated upon activation, normal T cell expressed, and secreted, (MIP-1): macrophage inflammatory protein 1)
Two companies that are pursuing Cytokine Therapies with a product of “Natural Mixtures of Cytokines.” They may provide the missing signal needed to raise the red flag, “The Danger Signal”
Multikine is in the Phase 3 and IRX-2 is in the Phase 1 clinical trial Phase
IRX Therapeutics seems to have the most appropriate mixture. Cel-SCI is missing the chemoattractants and proinflammatory cytokines.
If you combine the Cytokine therapy with anti-CTLA-4 blockage, will you get a synergistic immune response?
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B
