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Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 2-4 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Page 95 Current manufacturing processes for autologous cell-based cancer therapies are complex, slow, labor intensive, and expensive. These involve highly personalized methods requiring leukapheresis followed by ex vivo manipulation of cells before a therapy can be administered to the patient. While autologous cell-based therapies offer great promise for cancer treatment, there is growing concern that current manufacturing methods are unable to support the delivery of these treatments to the large numbers of patients eligible to receive them. In particular, the cell processing period between cell isolation and therapeutic administration, referred to as ‘vein-to-vein’ time, currently takes from 3-8 weeks. Using current methods, medical center laboratories that provide cell-based therapy often have the capacity to treat only 2-8 patients per month, which is insufficient to meet the high demand of clinical trials. Moreover, given that cell-based cancer therapy is still in its nascent stages, higher patient throughput is likely to accelerate the iterative bench-to-bedside-to-bench research that will be needed to improve and mature this treatment modality. There are several areas where innovation could improve the speed of autologous cell manufacturing, therefore reducing vein to vein time and increasing the number of patients that can be treated. Innovative solutions must propose a key bottleneck in the current system. Responsive proposals could develop systems capable of processing multiple patient samples simultaneously, modify current methods or systems to become novel point of care solutions, or address known release time bottlenecks such as developing rapid QC assays for sterility and potency. Ideal solutions will decrease both the time and cost required to deliver emerging autologous cell-based therapies to a greater number of patients, including those patients with rapidly progressing disease for whom autologous therapies may not currently be feasible. Proposed systems must be capable of optimizing and maintaining the desired physiological and immunological status of the expanded cells, while overcoming issues of cell senescence and exhaustion. Project Goals The overall goal of this solicitation is to stimulate the development of advanced manufacturing technologies that substantially improve the speed and cost of producing autologous cell-based therapies. Technical solutions are expected to address a key bottleneck in the current manufacturing process for individual cell-based therapies. Ideal solutions will involve parallel processing, rapid release testing, or point of care technology development, although other approaches may also be considered responsive. New technologies must produce cell-based products of equal or superior quality as compared to current manufacturing methods. The development of scalable systems capable of changing the number of cell products produced simultaneously, is strongly encouraged. For example, technologies may involve a modular engineering approach in which the system can be readily adapted as the demand for autologous cell therapies changes. To achieve the goals of the solicitation, offerors must be improving upon an existing end to end process that they have experience with, rather than developing end to end processes as part of the project. To be responsive, proposals must involve a collaboration between technology developers and clinical researchers with experience developing and treating patients with autologous cell-based cancer therapies. Projects also including an immunologist on the team will be prioritized. Phase I projects will be expected to involve feasibility testing of the proposed advanced manufacturing technology. A key activity during the Phase I project is to benchmark the novel advanced manufacturing approach against the current manufacturing method for a specific autologous cell-based product. More specifically, the research plan must include validating the proposed novel manufacturing approach against a process that has been used to produce product for clinical trials by demonstrating comparability of products with respect to specific critical quality attributes. Phase II projects will be expected to conduct full-scale processing to demonstrate a substantial increase in the speed and cost of producing autologous cell-based therapies. It is anticipated that most offerors will propose to study T-cell-based immunotherapy products, although other cell types are also encouraged (e.g., NK cells). Advanced manufacturing approaches may involve genetic engineering and optimization as appropriate for the cell-based therapy product, but the primary goal is to achieve substantial cost and throughput improvements for the overall vein-to-vein process. Activities not responsive to announcement: Projects proposing to use allogeneic cell-based therapies for technology validation will not be considered responsive under this solicitation. Projects improving a key part of the cell manufacturing process, but not being tested in an end to end process will be considered incomplete proposals and therefore not responsive to the topic. Phase I Activities and Deliverables: • Provide proof of collaboration with an immunologist(s), clinician(s), and an engineer(s) if device development activities are proposed. All collaborators must have experience developing high throughput systems and/or treating patients with autologous cell-based cancer therapies; • Establish assays and/or metrics, especially functional comparability and quality attributes, for benchmarking the approach against current manufacturing methods; • Establish defined specifications to enable integrated high throughput parallel manufacturing at faster speed and lower cost than current manufacturing methods; • Develop an early prototype device or technology for integrated high throughput autologous-cell manufacturing Page 96 that include specifications designed to substantially reducing the speed, as well as any cost savings based on the new manufacturing approach; • Demonstrate the suitability of the approach within the cell manufacturing process; • Demonstrate pilot-scale beta-testing of the approach comparing it against appropriate benchmarking technology; • Demonstrate the immunological functionality of the cells based on the previously identified functional comparability assays and/or metrics, and compare cell function to appropriate benchmarking technology; • Establish cell culturing technology compatible with high throughput production and technology to monitor the cells. Phase II Activities and Deliverables: • Develop an at-scale prototype of the approach with detailed specifications for hardware/software that supports the manufacturing of autologous cell therapies; • Generate scientific data demonstrating the proposed scalability (e.g. scale-out, point-of-use) of the technology and demonstrate cost and time improvements over current clinical standard; • Demonstrate comparable quality between the current manufacturing standard and cell-products manufactured at scale with the proposed approach.
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