Rationale for Eterna’s IL-7/IL-15 iMSC Cell Therapy (ERNA-101) in Solid Tumors
The approval of monoclonal antibody (mAb) agents, which inhibit T cell checkpoints (e.g. PD-1, CTL-4, LAG-3) have transformed current oncology practice, offering significant clinical benefit across a spectrum of solid tumor types. Unfortunately, in most instances, only a minority subpopulation of patients respond to these therapies [1, 2]. In the case of anti-PD-1 blockade, it has been well established that the patients who are most likely to benefit are those patients, whose tumors are heavily infiltrated with T cells – so called “hot” or inflamed tumors [3-5]. These patients seem to have mounted an immune response against the tumors, but the potentially efficacious tumor-specific cytotoxic effector T cells get “hung-up” on the T cell checkpoint (i.e PD-L1 in the tumor binds to PD-1 on the T cells, slamming on the “brakes”). Although anti-PD-1 mAbs have become the standard of care treatment across many tumor types, there remains significant room for improvement in terms of increasing the percentage of patients who respond (ORR), the durability of those responses (DOR) and the complete response (CR) rates[1].
A major determinant of treatment failure for immune-oncologic interventions lies in the strongly immunosuppressive tumor microenvironment itself, which can lead to impaired trafficking of T cells into tumors (i.e. immune exclusion) and decreased functionality of T cells (i.e. dysfunction/exhaustion) within the TME[5-7]. Hallmarks of T cell dysfunction include upregulation of multiple inhibitory molecules (e.g. PD-1, CTLA-4, etc), decreased ability to secrete inflammatory cytokines (e.g. IL-2, TNF, INFγ) upon antigen engagement, loss of cytotoxic functionality and aberrant expression of nuclear transcription factors (e.g. TOX) [6, 8]. Rudloff et al demonstrated that T cell dysfunction can begin to progress within hours of infiltration into the tumor[9].
The strong bias of the TME towards tolerance – through the mechanisms of immune exclusion and induced T cell dysfunction – offers an explanation for the lackluster performance of cancer vaccines to date as well as the general lack of efficacy seen with CAR-T therapies in solid tumors[10-14]. In both cases, the presence of significant numbers of tumor antigen-specific T cells in the periphery doesn’t equate to significant infiltration and anti-tumor activity of those T cells within the TME. An emerging consensus within the immune-oncology field is that T cell-focused therapeutics - including ICIs, vaccines and cell therapies – will require additional mechanisms that “soften” the tumor microenvironment for optimal therapeutic effect [15-18]. Considerable work in the field is focused on engineering such mechanisms into next-generation T cell products [19-25].
Eterna’s Solution: Leveraging the intrinsic tumor-homing ability of mesenchymal stem cells to create a Trojan Horse to soften the tumor microenvironment
Mesenchymal stem cells (MSCs) are known to home to and infiltrate into solid tumors[26-32]. Using our proprietary system for high-efficiency genetic engineering of induced pluripotent stem cells (iPSCs) and differentiation into MSCs, Eterna is capitalizing on this tumor-homing ability of MSCs to selectively deliver potent immunostimulatory factors into the tumor microenvironment with the goal of “softening” the TME. Our initial preclinical candidate in oncology is an iMSC, engineered to express two potent proinflammatory cytokines: IL-7 and IL-15. These two cytokines are known to help T cells proliferate, infiltrate into tumors and prevent premature exhaustion (for references, see below). Our therapeutic vision is that administration of our IL-7/IL-15 iMSCs will lead to highly selective expression of IL-7 and IL-15 in the tumor microenvironment, tipping the scale towards anti-cancer immunity, while limiting the untoward effects of systemic exposure and negative side effects.
IL-7: Overview
Interleukin 7 (IL-7) is a 4-alpha helix bundle cytokine of the IL-2 superfamily, which signals through the IL-7 receptor (IL-7R). IL-7R is itself composed of two discrete molecules: the common gamma chain receptor (CD132), which is a receptor component shared with other cytokine receptors (e.g. IL-2, IL-15) and IL-7Ra, which only binds to IL-7. Thus, the biologic effects of IL-7 are constrained by the presence of IL-7Ra, which is primarily expressed on lymphocytes, monocytes, macrophages, dendritic cells and NK cells. IL-7 is a critical cytokine supporting the development of multiple immune cell lineages, including B cells and T cells (CD4, CD8 and γδ). In addition to supporting the development of T cells, IL-7 is critical for the maintenance of naïve T cell populations in the periphery and expansion of T cell populations after lymphodepletion. IL-7 can also serve to promote differentiation of naïve T cells to memory T cells and enhance the proliferation and activity of effector T cells (reviewed [33]).
Preclinical studies in a variety of experimental tumor models showed that administration of IL-7 can lead to enhanced tumor growth control [34-37]. In some studies, the therapeutic benefit was associated with the expected treatment-related increase in anti-tumor T cell activity and immune cell infiltration into the tumors [38-40]. Il-7 has been administered as a recombinant cytokine in multiple clinical studies and has been demonstrated to be safe and generally well-tolerated [41, 42].
IL-15: Overview
Like IL-7, Il-15 is a member of the IL-2 cytokine superfamily, sharing the 4-alpha helix bundle structure common to the family but with unique biologic effects, including its ability to promote homeostatic and antigen-dependent proliferation, survival and enhanced effector function of CD8 T cells and NK cells[43, 44]. The IL-15 receptor is a heterotrimeric structure consisting of CD132 (the common gamma chain receptor), IL2R/IL15Rβ (CD122), and IL-15Rα [45]. Expression of the latter confers specificity of IL-15 activity [45]. Interestingly, IL-15 and IL-15Rα are usually expressed in the same cell, forming an intracellular heterodimer dimer, which is then either expressed on the cell surface or secreted [46]. In this manner, IL-15 is usually presented in trans, acting on cells, which express the heterodimeric CD122/CD132 receptor [47]. Numerous preclinical studies have demonstrated that IL-15 expands NK cells and antigen-specific CD8 T cells, increases their trafficking into tumors and significantly enhances anti-cancer immune responses in multiple immunocompetent syngeneic mouse models [48-55]. Not surprisingly, given this mechanism of action on T cells and NK cells, IL-15 has been shown to synergize with immune checkpoint inhibitors (e.g. PD-1 blockade), adoptive cell therapy with NK cells and tumor-specific CD8 T cells as well as with cancer vaccines [56-58]. Based on the positive data in these experimental models, IL-15 is currently being tested in a variety of therapeutic formats in ongoing clinical trials [58-60].
In summary, we anticipate that our engineered iMSCs will home to and infiltrate into the tumor stroma and selectively delivering IL-7 and IL-15 to the tumor microenvironment. In this way, Eterna’s IL-7/IL-15_iMSCs (ERNA-101) is expected to “soften” or convert the TME from an immunosuppressive state into an immunogenic one, leading to increased intratumoral recruitment of T and NK cells as well as enhanced proliferation, cytotoxic functionality and persistence of these cells within the TME. Based on this MOA, we anticipate that ERNA-101 will lead to improved therapeutic outcomes as a monotherapy (in tumors where sufficient endogenous antigen-specific T cells are present) as well as in combination with other T cell-focused therapeutics, including ICIs, bispecific T cell engagers (BiTEs), cancer vaccines, TILs (tumor infiltrating lymphocytes) and other T cell products (e.g. CAR-Ts, transgenic TCRs).
Based on these data and our ongoing preclinical studies, we anticipate that Eterna’s IL-7/IL-15 iMSCs (ERNA-101) will successfully engraft into ovarian cancer tumor deposits and trigger effective and durable anti-cancer immune responses.
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