MANF

A new preclinical study has discovered the underlying cause of gender differences in immunotherapy-associated myocarditis after immune checkpoint inhibitor (ICI) treatment. Their findings point to possible treatment strategies for this side effect, which disproportionately affects female patients. A new preclinical study from researchers at The University of Texas MD Anderson Cancer Center and the University of California San Francisco (UCSF) has discovered the underlying cause of gender differences in immunotherapy-associated myocarditis after immune checkpoint inhibitor (ICI) treatment. Their findings point to possible treatment strategies for this side effect, which disproportionately affects female patients. The study, published today in Science Translational Medicine, demonstrates how life-saving ICI treatment reduces levels of estrogen and important heart-protective proteins, sometimes leading to cardiovascular complications. The results suggest several treatment approaches, including hormone therapies, that could target this endocrine-cardiac-immune pathway without affecting treatment responses. "Immune checkpoint inhibitors can be life-saving for many patients, but increasing the dose or combining with other therapies also increases the risk for myocarditis, particularly in women," said co-corresponding author Liuqing Yang, Ph.D., associate professor of Molecular and Cellular Oncology. "With this study, we now understand the mechanisms behind this, and we've found several potential ways to reduce this risk without compromising the antitumor effects of treatment." Immune checkpoint inhibitors result in durable anti-tumor responses in many patients, but they are associated with an increased risk of cardiovascular toxicities caused by immune cells that infiltrate heart tissue. While this occurs in only about 1% of patients, these side effects can significantly increase the mortality rate in women. To better understand the mechanisms behind these gender differences, Yang worked with co-corresponding authors Chunru Lin, M.D., Ph.D., associate professor of Molecular and Cellular Oncology at MD Anderson, and Javid Moslehi, M.D., associate professor of Cardio-Oncology and Immunology for the UCSF Heart and Vascular Center. Checkpoint blockade reduces expression of heart-protective genes, particularly in females MD Anderson researchers collaborated with Moslehi and his team at UCSF to develop laboratory models of melanoma, breast and colorectal cancer to study ICI-associated myocarditis. Treatment with commonly used ICIs (anti-PD-1 and anti-CTLA-4 antibodies) inhibited tumor growth but also increased immune cell infiltration, particularly in female hearts, causing electrocardiographic abnormalities and systolic dysfunction associated with myocarditis. By studying these models, the team discovered that ICI treatment decreased expression of Manf and Hspa5 genes in heart tissue, especially in females. Similarly, models lacking the immune checkpoint genes Ctla4 and Pdcd1 also had a pronounced increase in heart-infiltrating immune cells and a lower expression of Manf and Hspa5. Further investigation revealed the same pattern in patients with ICI-associated myocarditis, where MANF and HSPA5 proteins were decreased and immune cells were elevated compared to healthy donors. These findings suggest that MANF and HSPA5 are involved in regulating interactions between the cardiovascular and immune systems. Infusions of recombinant MANF and HSPA5 proteins reversed these effects, improving cardiac function without affecting antitumor response after ICI, highlighting this as a possible therapeutic strategy. ICI treatment influences sex hormone levels, suggesting possible treatment approaches "The sex differences observed in both ICI-myocarditis mouse models are especially intriguing because in non-ICI myocarditis (viral or autoimmune) in the general population, male sex is considered a risk factor and defines a more severe course," Moslehi said. "If such an opposite sex difference in ICI-myocarditis is true, it suggests a possible interaction of immune checkpoints and sex hormones." Indeed, the researchers noted that serum concentrations of estrogen were significantly reduced in both males and females two weeks after ICI treatment, along with downregulation of Manf and Hspa5. Using an estrogen receptor β (ERβ) agonist to increase estrogen-dependent expression of Manf and Hspa5 resulted in tumor shrinkage and a decrease in heart-infiltrating immune cells following ICI treatment. Conversely, androgen deprivation therapy increased expression of these proteins and proved successful in laboratory models as an alternative strategy to lessen myocarditis. "Based on these results, we can envision several potential treatment strategies. For example, we may consider monitoring estrogen levels in patients after ICI treatment and potentially infusing them with recombinant MANF and HSPA5 proteins to bring their levels back up and improve outcomes," Lin said. "Likewise, targeting with an ERβ agonist to increase expression of Manf and Hspa5, or blocking androgens to do the same, might reduce the risk of adverse events, allowing us to tailor these strategies to individual patient needs so we can optimize the use of immunotherapy and minimize cardiac toxicities." While this is a preclinical study, the authors are planning clinical trials to evaluate these approaches using drugs already approved by the Federal Drug Administration (FDA). This work was supported by MD Anderson institutional funding, the Cancer Prevention and Research Institute of Texas (CPRIT) (RP200423, RP180259), an American Association for Cancer Research (AACR)-The Mark Foundation for Cancer Research Science of the Patient Grant, the National Institutes of Health (R01CA218025, R01CA231011, R01HL141466, R01HL155990, R01HL156021), and the U.S. Department of Defense (BC180196).

- Aims to develop an immune-evasive stem cell therapy as a potentially curative treatment for diabetes - - Parties will collaborate through commercialization and share costs and profits worldwide - ZUG, Switzerland and CAMBRIDGE, Mass. and SAN DIEGO, Sept. 17, 2018 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (NASDAQ: CRSP), a biopharmaceutical company focused on developing transformative gene-based medicines for serious diseases, and ViaCyte, Inc., a privately held regenerative medicine company, today announced a collaboration focused on the discovery, development, and commercialization of gene-edited allogeneic stem cell therapies for the treatment of diabetes. Decades of clinical data with islet transplants indicate that beta-cell replacement approaches may offer curative benefit to patients with insulin-requiring diabetes. ViaCyte has pioneered the approach of generating pancreatic-lineage cells from stem cells and delivering them safely and efficiently to patients. PEC-Direct, ViaCyte’s lead product candidate currently being evaluated in the clinic, uses a non-immunoprotective delivery device that permits direct vascularization of the cell therapy. This approach has the potential to deliver durable benefit; however, because the patient’s immune system will identify these cells as foreign, PEC-Direct will require long-term immunosuppression to avoid rejection. As a result, PEC-Direct is being developed as a therapy for the subset of patients with type 1 diabetes at high risk for acute complications. CRISPR gene editing offers the potential to protect the transplanted cells from the patient’s immune system by ex vivo editing immune-modulatory genes within the stem cell line used to produce the pancreatic-lineage cells. The speed, specificity, and multiplexing efficiency of the CRISPR system make it ideally suited to this task. CRISPR Therapeutics is pursuing a similar approach for its allogeneic CAR-T programs and has established significant expertise in immune-evasive gene editing. The combination of ViaCyte’s stem cell capabilities and CRISPR’s gene editing capabilities has the potential to enable a beta-cell replacement product that may deliver durable benefit to patients without triggering an immune reaction. “We believe the combination of regenerative medicine and gene editing has the potential to offer durable, curative therapies to patients in many different diseases, including common chronic disorders like insulin-requiring diabetes. ViaCyte is a pioneer in the regenerative medicine field, and has built a compelling clinical program, robust manufacturing capabilities, and assembled a strong intellectual property position. Partnering with ViaCyte will allow us to accelerate our efforts in regenerative medicine, an area that we believe will provide a variety of longer-term opportunities for our company,” commented Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. Under the terms of the agreement, CRISPR and ViaCyte will jointly seek to develop an immune-evasive stem cell line as a first step on the path to an allogeneic stem-cell derived product. Upon successful completion of these studies and identification of a product candidate, the parties will jointly assume responsibility for further development and commercialization worldwide. Upon execution of the agreement ViaCyte will receive $15 million from CRISPR, which at CRISPR’s election may be paid in either cash or CRISPR stock. ViaCyte also has the option, under certain circumstances, to receive an additional $10 million from CRISPR in the form of a convertible promissory note. “Creating an immune-evasive gene-edited version of our technology would enable us to address a larger patient population than we could with a product requiring immunosuppression. CRISPR Therapeutics is the ideal partner for this program given their leading gene editing technology and expertise and focus on immune-evasive editing. We are thrilled to have the opportunity to partner with CRISPR Therapeutics on what we believe could be a transformational therapy for patients with insulin-requiring diabetes,” commented Paul Laikind, Ph.D., Chief Executive Officer and President of ViaCyte. “We also believe that this approach may have many other applications which we and CRISPR may explore in the future.” About CRISPR Therapeutics CRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic collaborations with leading companies including Bayer AG and Vertex Pharmaceuticals. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts, and business offices in London, United Kingdom. For more information, please visit www.crisprtx.com. About ViaCyte ViaCyte is a privately-held regenerative medicine company developing novel cell replacement therapies as potential long-term diabetes treatments to achieve glucose control targets and reduce the risk of hypoglycemia and diabetes-related complications. ViaCyte’s product candidates are based on the derivation of pancreatic progenitor cells from stem cells, which are then implanted in durable and retrievable cell delivery devices. Once implanted and matured, these cells are designed to secrete insulin and other pancreatic hormones in response to blood glucose levels. ViaCyte has two product candidates in clinical-stage development. The PEC-Direct™ product candidate delivers the pancreatic progenitor cells in a non-immunoprotective device and is being developed for type 1 diabetes patients who have hypoglycemia unawareness, extreme glycemic lability, and/or recurrent severe hypoglycemic episodes. The PEC-Encap™ (also known as VC-01) product candidate delivers the same pancreatic progenitor cells in an immunoprotective device and is being developed for all patients with diabetes, type 1 and type 2, who use insulin. ViaCyte is also seeking to develop immune-evasive ‘universal donor’ stem cell lines, from its proprietary CyT49 cell line, which are expected to further broaden the availability of cell therapy for diabetes and other potential indications. ViaCyte is headquartered in San Diego, California. ViaCyte is funded in part by the California Institute for Regenerative Medicine (CIRM) and JDRF. For more information, please visit www.viacyte.com. CRISPR Forward-Looking Statement Certain statements set forth in this press release constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the timing of filing of clinical trial applications and INDs, any approvals thereof and timing of commencement of clinical trials, the intellectual property coverage and positions of CRISPR Therapeutics, its licensors and third parties, the sufficiency of CRISPR Therapeutics’ cash resources and the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, the forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: uncertainties regarding the intellectual property protection for our technology and intellectual property belonging to third parties; uncertainties inherent in the initiation and completion of preclinical studies for CRISPR Therapeutics’ product candidates; availability and timing of results from preclinical studies; whether results from a preclinical trial will be predictive of future results of the future trials; expectations for regulatory approvals to conduct trials or to market products; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics’ most recent annual report on Form 10-K, and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC's website at www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law. CRISPR Media Contact: Jennifer Paganelli WCG on behalf of CRISPR 347-658-8290 jpaganelli@wcgworld.com CRISPR Investor Contact: Susan Kim 617-307-7503 susan.kim@crisprtx.com ViaCyte Media Contact: Jessica Yingling, Ph.D. Little Dog Communications, Inc. 858-344-8091 jessica@litldog.com ViaCyte Investor Contact: Eugene Brandon, Ph.D. 858-455-3708 ebrandon@viacyte.com Source: CRISPR Therapeutics AG