Blockchain Papers

Ching Lam, Michelle Helena van Velthoven, Edward Meinert

BACKGROUND: Advanced therapies, including cell and gene therapies, have shown therapeutic promise in curing life-threatening diseases, such as leukemia and lymphoma. However, these therapies can be complicated and expensive to deliver due to their sensitivity to environment; troublesome tissue, cell, or genetic material sourcing; and complicated regulatory requirements. OBJECTIVE: This study aims to create a novel connected supply chain logistics and manufacturing management platform based on blockchain, with cell and gene therapy as a use case. Objectives are to define the requirements and perform feasibility evaluations on the use of blockchain for standardized manufacturing and establishment of a chain of custody for the needle-to-needle delivery of autologous cell and gene therapies. A way of lowering overall regulatory compliance costs for running a network of facilities operating similar or parallel processes will be evaluated by lowering the monitoring costs through publishing zero-knowledge proofs and product release by exception. METHODS: The study will use blockchain technologies to digitally connect and integrate supply chain with manufacturing to address the security, scheduling, and communication issues between advanced therapy treatment centers and manufacturing facilities in order to realize a transparent, secure, automated, and cost-effective solution to the delivery of these life-saving therapies. An agile software development methodology will be used to develop, implement, and evaluate the system. The system will adhere to the EU and US good manufacturing practices and regulatory requirements. RESULTS: This is a proposed study protocol, and upon acceptance, grant funding will be pursued for its execution in 2021. CONCLUSIONS: The successful implementation of the integrated blockchain solution to supply chain and manufacturing of advanced therapies can push the industry standards toward a safer and more secure therapy delivery process. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/17005.

Marie Recine

The atmosphere at the 5th Annual Immuno-Oncology 360° (IO360°) Conference, which took place on February 6–8 at the Crowne Plaza Times Square in New York City, was truly collaborative. Co-chaired by Axel Hoos, MD, PhD (GSK), James Gulley, MD, PhD (National Cancer Institute [NCI]), and Andrew Baum, MD (Citi), the conference featured almost 100 speakers and 10 plenary sessions, including 4 keynote talks and 7 panel discussions. More than 400 attendees representing the pharma, biotech, academic, regulatory, and private investment communities gathered to discuss the rapid advancement in scientific, clinical, and business developments in IO, with the goal of accelerating the development of new therapeutics for patients. Over 350 partnering meetings took place over the 3-day conference.“360 degrees means we really want to speak to all stakeholders,” stated Dr. Hoos. The meeting is structured for the scientists to bring their most promising next-generation mechanisms that will help address these challenges. However, it is also important to look at therapies that haven't worked, so we don't repeat the same challenges of the past, he noted. “But IO360° is not just the science, it's about the entire ecosystem in which the science exists, and that includes the patients and those that provide the funding to make the science happen.”Michel Sadelain, MD, PhD, of Memorial Sloan Kettering Cancer Center, opened the meeting with a keynote, Chimeric Antigen Receptor (CAR) - T Cell Therapy and the CD19 Paradigm. With two CD19 CAR-T cells (CAR Ts) approved in 2017, Dr. Sadelain identified three new directions being taken to optimize CAR T therapy and develop next-generation CAR Ts. The first is addressing exhaustion (loss of functionality) using genome engineering at a carefully select locus (TRAC) to create more potent CAR Ts and incorporating new designs that modify the activating portion of the CAR and balance rapid expansion and retained memory (1XX CAR). The second is gaining insight into the pathophysiology of cytokine release syndrome, including CAR T–macrophage interactions, to try and reduce toxicity. The third is employing new strategies for circumventing antigen escape, such as use of radiosensitization and combinatorial targeting.The Discovery and Preclinical Science plenary focused on strategies being investigated to modify the tumor microenvironment and address limitations of patient-sourced therapies. According to the plenary chair, Ronald Herbst, PhD, “we are all excited about the potential for immunotherapy for patients with cancer, but many patients don't respond to checkpoint inhibitors.” Part of the problem is explained by the fact that “immune contexture varies within and across tumor types, and so-called ‘hot’ versus ‘cold’ tumors,” he noted. In order to increase the efficacy of immunotherapy, a number of areas are actively being targeted, including antigen presentation, innate mechanisms of activation, the tumor microenvironment, and overcoming immunosuppression.A variety of cells, growth factors, and cytokines in the tumor microenvironment play a pivotal role in whether or not immunotherapy is effective. Various strategies are being employed that attempt to modify the tumor microenvironment to overcome immunosuppressive mechanisms, such as blocking adenosine with an anti-CD73 monoclonal antibody (oleclumab, Medimmune) or an A2A receptor antagonist (CPI-144, Corvus), or inhibiting the IDO (indoleamine 2,3-dioxygenase) pathway (indoximod, NewLink Genetics). Other strategies are being employed to enhance the efficacy of cytokines to augment the expansion and activation of T cells, such as engineering enhanced versions of growth factors such as interleukin-2 (IL-2; NKTR-214, Nektar, and MDNA109, Medicenna) and IL-10 (pegilodecakin, ARMO). For example, pegilodecakin, a long-acting pegylated form of IL-10, induces hallmarks of CD8+ T cell immunity in cancer patients. According to Aung Naing, MD, and Martin Oft, MD, pegilodecakin demonstrated clinical benefit in studies as a single agent and in combination with both chemotherapy and checkpoint inhibitors across several tumor types. The agent is currently being investigated in a Phase 3 trial in metastatic pancreatic cancer.Off-the-shelf hematopoietic cell products are being developed to address some of the limitations of patient-sourced cell therapies, such as heterogeneity, single-patient manufacturing, need for sufficient cells, extended production time, and cost. For example, engineered CAR natural killer cells, derived from induced pluripotent stem cells, are being developed that incorporate several individual components that together help to enhance persistence and antitumor efficacy (FT596, Fate Therapeutics). Multicombinatorial strategies such as this may be key in reigniting the endogenous immune system and improving efficacy in solid tumor space.Genentech's Priti Hegde, PhD, opened the Translational Science and Emerging Biomarkers plenary, part 1, with a keynote, Biomarker Signaling: Turning Cold Tumors Hot. Individual cancer types can be characterized along the tumor immunity continuum based on immune phenotype (i.e. inflamed or noninflamed) and tumor mutational burden (TMB). How can we generate an immune response signal in noninflamed tumors when most do not achieve the TMB threshold that selects for benefit? Dr. Hedge highlighted two approaches: adaptive immunity, which has the potential to drive memory response, and synthetic immunity, which has the potential to sustain efficacy and drive log kill. An example of an adaptive immunity approach is neoantigen-specific T-cell therapy, in which there are limited but encouraging data demonstrating its ability to promote adaptive immunity in noninflamed tumors. Synthetic immunity approaches include engineered T cells (e.g. NY-ESO SPEAR T cells [GSK/Adaptimmune], BMCA CAR Ts) and bi-specific biologics (e.g. antibodies, BITEs® [Amgen], ImmTAC® [Immunocore]), in which there is a proof of concept that these approaches are feasible in solid tumors and checkpoint inhibitor-refractory hematologic malignancies.One may also need to address the underlying biology to turn cold tumors hot. According to Dr. Hegde, the future of immunotherapy may be highly personalized, and one will need to look at a variety of markers in biopsy specimens using a variety of techniques. This will only be possible if we have: (1) a tissue-conserving, regulatory-grade decentralized platform to be able to run all of these assays in trials and (2) trial designs and statistical analysis plans that enable diagnostic signal-seeking validation and a path for registration.The remainder of the plenary reported on translational data and evolving biomarkers and applications to help support decision-making for IO drug development.Negative results from the Phase 3 study of the therapeutic prostate cancer vaccine PROSTVAC (Bavarian Nordic) show that a combinatorial approach may be needed with vaccines. Similarly, oncolytic viruses may need multiple transgenes and mechanisms to reverse complex immunosuppressive microenvironments. To address this issue, T-Stealth™ oncolytic viruses (BeneVir) can incorporate multiple genes, evade clearance by the innate and adaptive immune systems, and be combined with other drugs and IO agents.With the increasing need for biomarker support, the clinical trial laboratory reality in the IO space is complex. Patrice Hugo, PhD (Q2 Solutions), summarized important features to consider when selecting a lab partner for drug development. Key strategies to successfully introduce innovation in the clinical trial lab space include joint review of pros and cons of technologies, consideration of joint investments, performing Phase 1 specialized testing in niche labs/academic settings with transfer to a central lab, and discussion and planning for regulatory requirements.Advances in positron emission tomography (PET) imaging and radiomics provide a quantitative, noninvasive way to assess the dynamic changes of the immune system. For example, CD8 PET (Imaging Endpoints) may help distinguish between hot and cold tumors and address fundamental questions regarding the role of CD8 cells in the tumor microenvironment.Other unique biomarkers and applications under investigation include MultiOmyx™ (NeoGenomics), a proprietary multi “omic” technology that enables detection and visualization of up to 60 biomarkers on a single slide; immunosequencing (immunoSEQ, Adaptive Biotechnologies), a clinical diagnostic for monitoring clonal expansion and predicting/evaluating response to therapy that can also be used in combination with cellular immunology and computational biology (Multiplexed Identification of T cell Receptor Antigen [MIRA] assay, Adaptive Biotechnologies) to map T-cell receptors; and CANscript™ (Mitra), a personalized ex vivo histoculture approach that can be used to evaluate drug-induced modulation of the tumor microenvironment and predict clinical performance.The IO Novel Technologies and Innovative Solutions plenary showcased companies that have technologies and solutions that will help stakeholders in the IO field advance developments for cancer therapeutics. Presenters included Advaxis, Bioxcel Therapeutics, IAG, Provecs Medical, Rgenix, and Sensei Bio.Andrew Baum, MD (Citi), opened the Financial and Commercial Implications plenary with a keynote, Evaluation and Forecast of the IO Space. He started off by discussing key questions on health-care investors' minds. According to Dr. Baum, “what investors don't like very much about IO is that the technology cycles are short, so you can go from here to zero very quickly very easily.” He cited ipilimumab and the fact that it was quickly eclipsed by anti-PD (L)-1 agents. Another issue is the “paradox of choice,” as there are so many different modalities. “It's almost overwhelming,” he noted, “especially for someone that doesn't have a deep scientific background to interpret a Phase one trial.” Other questions involve primary and secondary resistance, cell therapy manufacturing constraints, minimizing/managing toxicity, and financial toxicity. However, despite these questions, “the good news is the amount of capital, the enthusiasm, and the scientific advancement all mean that we're going to make huge strides in IO, I have no doubt.”Dr. Baum stressed the importance of learning from historic disappointments and noted that we need better biomarkers, better trials, and patience so that the benefits can be extended to more patients. He ended his presentation with a slide showing Citi's top 10 novel IO targets for 2020, in which IL-2/IL-15 took the top spot.Khalil Barrage (Invus) agreed that the IO revolution has led to unprecedented investor enthusiasm for oncology, unlocking massive commercial opportunities. However, the discovery of checkpoints and their curative potential has led to hype in IO drug discovery, resulting in risky behavior. In addition, the flood of capital has lowered potential returns and there are a lot of IO agents in development with poorly validated rationale. As a result, Invus' approach to investing incorporates strategies such as diversification, selectivity, exploring synergistic opportunities, investing where innovation is happening, paying a premium for validated approaches when warranted, and assessing reimbursement.The plenary concluded with a panel discussion on monetizing science: the preparation of an IPO, straight licensing with the transition to a public company, and decision-making on prioritization within portfolios. Key takeaways included strategies for building out scientific and executive talent, the importance of having a scientific advisory board to test out the research, and being prepared to be a public company.The Trends and Collaborations plenary featured presentations by three major industry media companies in the IO field, which discussed new trends and their effect on the investment landscape.BioCentury analyzes IO trends at recent medical meetings using machine learning, began Simone Fishburn, PhD, VP, and Executive Editor. Despite the huge focus on PD (L)-1, academics and companies are aggressively looking for, and finding new targets, with LAG3 topping the list in company oncology pipelines in 2019. CAR T activity is moving into solid tumors, with new constructs and multiple tumor antigens targeted. Immunometabolism and tumor mutation burden are hot topics. Funding for IO start-ups is outstripping other areas, both inside and outside oncology, drawing traditional and corporate investors.According to John D. Carroll (Endpoints News), these trends are supported by global data published by the Cancer Research Institute, which show that there were 3394 IO agents representing 417 targets in the pipeline in 2018, representing a 67% increase over 2017.How are these trends affecting the investment landscape? According to Jeff Bockman, PhD (Cello Health BioConsulting), IO dominates oncology growth, but not sales. Moreover, although IO deals have shown evidence of slowing, whether due to maturation, saturation, or fatigue, and oncology and IO investments remain robust.The Business Development plenary, hosted by Solebury Trout, included panel discussions on partnering, fundraising, and rational investing. The first panel discussed IO partnering strategies from the viewpoint of pharma and academia. According to Dr. Hoos, who the partnering in this space have but there has much and is only that companies have started their unique which will a partnering the for is tumor and the and the companies on the panel and there to be both and with some moving from and on those that can IO and agents are being by most in the and are to play which was for and discussed in the IO space and a number of For example, the panel stressed the importance of at and and on key and as a private on their ecosystem their investors with in the past, key to their than at with the top at the with key the of and companies introduce than need to so that can panel focused on IO investment investors this an time, with a future for many modalities. 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As a result, trends include the use of immune response machine learning to the of imaging and new techniques. 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The agent has across more than including in is moving into the of therapy, and next-generation biomarkers are to help promising were also for a a and combination immunotherapy and the tumor receptor has to more benefit in Dr. Hoos. However, there is a lot of As a result, “we need to new to the benefit PD Cell therapy has really to the of engineered and we are to the benefit from to solid tumors and overcoming the such as T-cell that in the for patients is