Our Pipeline
*Alone or in combination with immunotherapies (CAR-T, bispecific T-cell engagers, checkpoint inhibitors, tumor-infiltrating lymphocytes, etc.) with potential big-pharma collaborators
*Alone or in combination with immunotherapies (CAR-T, bispecific T-cell engagers, checkpoint inhibitors, tumor-infiltrating lymphocytes, etc.) with potential big-pharma collaborators
ERNA-101*
Oncology
Platinum-Resistant Ovarian Cancer
ERNA-201
Autoimmune Disease
Rheumatoid Arthritis
Despite recent advances in therapy, ovarian carcinoma remains the most lethal of gynecologic malignancies with approximately 13,000 deaths/year (2022) in the USA[1]. High-grade serous carcinoma (HGSOC) represents the most frequent histologic type of ovarian cancer and typically presents at an advanced stage due with symptomology reflecting disseminated intraperitoneal spread: abdominal pain and distension , difficulty eating, ascites, urinary complaints and shortness of breath[2]. Although these tumors typically respond initially to surgical resection and platinum-based chemotherapy, over 80% of patients recur and greater than 50% of patients will succumb to their disease within 5 years of diagnosis[3]. Interestingly, high baseline levels of proinflammatory cytokines, including Il-7, correlate with an inflamed tumor microenvironment and better PFS following standard-of-care treatment[4]. Thus, there remains a significant unmet medical need for patients with platinum-resistant ovarian carcinoma and a rationale for new therapeutics to enhance inflammation in the ovarian tumor microenvironment.
Ovarian carcinoma is thought to be immunogenic based on a high frequency of PD-1 and PD-L1 expression, the presence of TILS and the correlation of TILs with improved clinical outcomes[5-10]. Surprisingly, the response to ICIs has been underwhelming. In a Phase 2 trial with 366 Ovarian Cancer patients testing the efficacy of pembrolizumab (KeytrudaTM), objective response rates were 7.4% overall[11]. Results were similarly disappointing in the Phase 3 trial with nivolumab (OptivoTM)in platinum-resistant ovarian cancer (8% ORR) without any observed improvement in either PFS or OS[12]. A likely reason contributing to this overall lack of meaningful clinical response to ICIs is the prevalence of immunosuppressive myeloid cells, regulatory T cells (Tregs) and immunosuppressive cytokines within the HGSOC tumor microenvironment, leading to both immune cell exclusion and dysfunction [13-15].
One of our collaborators, Dr. Michael Andreeff (MD Anderson), has pioneered the use of gene-modified MSCs as a potential therapy for ovarian cancer. Dr. Andreeff and colleagues demonstrated in several experimental mouse tumor models that intraperitoneal injection of MSCs engineered to express interferon beta (INFβ) were capable of engrafting into peritoneal tumor deposits with persistent secretion of INFβ, both in human xenograft tumor models and in a syngeneic ID8 tumor model using immunocompetent mice. A significant improvement in tumor burden and survival was observed in all of these experimental systems[16]. A subsequent single-site Phase 1 clinical trial was initiated at MD Anderson in patients with advanced platinum-refractory ovarian cancer to evaluate the safety, feasibility and tumor response to intraperitoneal-administered INFβ-MSCs. In the first cohort, INFβ-MSCs were dosed weekly with 1x105 MSCs/kg with a total of 4 doses. Histologic analysis confirmed that the INFβ-MSCs were able to colonize tumor sites and express INFβ locally[17]. Although no objective responses were identified at this first dose level, this study demonstrates the feasibility of intraperitoneal delivery of MSCs as a treatment modality in patients with advanced ovarian cancer.
References
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases with an estimated global prevalence of approximately 2%[1]. RA is driven by chronic autoimmune-mediated inflammation of the joints (i.e. synovitis), mainly affecting small joints, causing pain, swelling, joint destruction and considerable morbidity. Although significant progress has been made in the treatment of RA, considerable unmet medical need persists with a significant fraction of patients suffering from difficult-to-treat (D2T) RA. A variety of cell-based therapies are currently in development to address this need, including chimeric antigen-receptor transgenic T cells (CAR-Ts), adoptive transfer of regulatory T cells (Tregs), including CAR-Tregs, tolerogenic dendritic cell “vaccines” and mesenchymal stem cells (MSCs)[2-6].
Mesenchymal stem cell therapy has been demonstrated to be an effective treatment in numerous preclinical rodent models of autoimmune arthritis[7-12]. Based on these impressive preclinical results, mesenchymal stem cells have been administered to patients with rheumatoid arthritis in several early clinical trials (reviewed[2]. In general, these studies have demonstrated that MSCs administration is safe and well-tolerated. Several studies have demonstrated improvements in symptomology as well as biochemical evidence of decreased inflammation[13-15].
In RA, we anticipate that our synthetic allogeneic induced pluripotent stem cell (iPSC)-derived MSC product (ERNA-201) will exhibit superior anti-inflammatory functionality and disease modifying effects as compared to these prior “native” MSC therapies due to several key factors, including: clonality (i.e. uniformity) of the product, ease of manufacturing, enhanced proliferative capacity, increased immunosuppressive IDO-1 expression, decreased immunogenicity and engineered secretion of the potent immunoregulatory cytokine, IL-10. As described above, we anticipate that ERNA-201 will strongly re-polarize macrophages and, consequently, the synovial microenvironment, towards an anti-inflammatory/regenerative state.
References
1. Black, R.J., et al., Global, regional, and national burden of rheumatoid arthritis, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. The Lancet Rheumatology, 2023. 5(10): p. e594-e610.
2. Li, Y.J. and Z. Chen, Cell-based therapies for rheumatoid arthritis: opportunities and challenges. Ther Adv Musculoskelet Dis, 2022. 14: p. 1759720X221100294.
3. Rai, V., et al., Futuristic Novel Therapeutic Approaches in the Treatment of Rheumatoid Arthritis. Cureus, 2023. 15(11): p. e49738.
4. He, N., et al., Mesenchymal stem cell-derived extracellular vesicles targeting irradiated intestine exert therapeutic effects. Theranostics, 2024. 14(14): p. 5492-5511.
5. Shimizu, Y., et al., Optimizing mesenchymal stem cell extracellular vesicles for chronic wound healing: Bioengineering, standardization, and safety. Regen Ther, 2024. 26: p. 260-274.
6. Stoppelenburg, A.J., et al., Design of TOLERANT: phase I/II safety assessment of intranodal administration of HSP70/mB29a self-peptide antigen-loaded autologous tolerogenic dendritic cells in patients with rheumatoid arthritis. BMJ Open, 2024. 14(9): p. e078231.
7. Nam, Y., et al., Intraperitoneal infusion of mesenchymal stem cell attenuates severity of collagen antibody induced arthritis. PLoS One, 2018. 13(6): p. e0198740.
8. Shu, J., et al., Transplantation of human amnion mesenchymal cells attenuates the disease development in rats with collagen-induced arthritis. Clin Exp Rheumatol, 2015. 33(4): p. 484-90.
9. Li, X., et al., Human Umbilical Mesenchymal Stem Cells Display Therapeutic Potential in Rheumatoid Arthritis by Regulating Interactions Between Immunity and Gut Microbiota via the Aryl Hydrocarbon Receptor. Front Cell Dev Biol, 2020. 8: p. 131.
10. Abdelmawgoud, H. and A. Saleh, Anti-inflammatory and antioxidant effects of mesenchymal and hematopoietic stem cells in a rheumatoid arthritis rat model. Adv Clin Exp Med, 2018. 27(7): p. 873-880.
11. Jung, N., et al., LC-MS/MS-based serum proteomics reveals a distinctive signature in a rheumatoid arthritis mouse model after treatment with mesenchymal stem cells. PLoS One, 2022. 17(11): p. e0277218.
12. El-Gendy, H., et al., Comparative study between human mesenchymal stem cells and etanercept as immunomodulatory agents in rat model of rheumatoid arthritis. Immunol Res, 2020. 68(5): p. 255-268.
13. Yang, Y., et al., Serum IFN-gamma levels predict the therapeutic effect of mesenchymal stem cell transplantation in active rheumatoid arthritis. J Transl Med, 2018. 16(1): p. 165.
14. Wang, L., et al., Efficacy and Safety of Umbilical Cord Mesenchymal Stem Cell Therapy for Rheumatoid Arthritis Patients: A Prospective Phase I/II Study. Drug Des Devel Ther, 2019. 13: p. 4331-4340.
15. Alvaro-Gracia, J.M., et al., Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis, 2017. 76(1): p. 196-202.
