Cell Manipulation Core

The Connell and O'Reilly Families Cell Manipulation Core Facility (CMCF) assists HCC members in developing new cell-based therapies for patients with cancer who are enrolled in novel therapeutic clinical research protocols.

Publication Acknowledgement

If research supported by this core facility results in publication, please acknowledge this support by including the following in your publication(s):

We thank Harvard Cancer Consortium in Boston, MA, for the use of the Cell Manipulation Core, which provided ______________________________ service. Harvard Cancer Consortium is supported in part by a NCI Cancer Center Support Grant # NIH 5 P30 CA06516.

Core services include processing of hematopoietic stem cells for autologous or allogeneic transplantation, genetic modification of hematopoietic stem cells, generation of tumor vaccines, and manufacture of genetically modified immune cells for adoptive cellular therapy. The core also collects and stores follow-up blood and bone marrow samples from subjects treated on cell therapy protocols, thus providing an additional service to clinical investigators, ensuring that all research objectives of clinical protocols are met.

Pricing varies; contact the Core for details.

Key services of the Core include:

• Production of cellular products for patients enrolled on clinical research protocols
  • Hematopoietic stem cells
  • Tumor cell vaccines
  • Dendritic cell vaccines
  • Adoptive Cellular Therapy Components
• Cell therapy process development, consultation, and support
  • Develop manufacturing SOPs
  • Validate processes and SOPs
  • Build and activate templates for orders to manufacture, collect, process, and release cellular products to patients (Biotherapy Order Entry, BOE)
• Clinical trial development consultation for cellular therapeutic studies
  • Pre-clinical development and trial design
  • DF/HCC and FDA Review
  • Data management
  • Quality control
  • Internal and external audits
  • Reports and publications
• Regulatory (internal and external) consultation and support
  • Assist with pre-IND FDA meetings
  • Assist with Chemistry, Manufacturing, and Controls (CMC) section of -IND preparation and patient consents
  • Assist PI with amendments and annual reports
  • Assist with IRB protocol submission
  • Review and sign-off on all protocols
  • Audit all IND/IDE manufacturing for compliance with IND/IDE and protocol
  • Prepare for FDA and Sponsor audits
• Quality control (assays and testing)
• Quality assurance
  • Regulatory (FDA) and accreditation (FACT & JC) compliance monitoring
  • Audit and review procedures, processes, and test results
  • Assist with labeling requirements
  • Monitor product non-conformances
• Cellular product manufacturing, characterization, storage, and distribution
• Pre- and post-treatment processing and banking of patient samples

The CMCF currently supports more than 40 diverse active clinical research protocols, with a focus on translational research in the immune therapy of cancer. Many of these clinical trials and therapies could not have been carried out without the cell manufacturing and regulatory support provided by the Core.

CMCF Support for Clinical Trials

• 24 trials supported with CMCF Investigationalmanufactured products​
• CAR-T (11)​
• Genetically modified stem cells (4)​
• NK selection / activation (6)​
• T-regulatory cells (2)​
• iPSC-derived dopaminergic neurons (1)​
• 12 trials supported with standard of care products​
• 29 trials supported with products manufactured atother/commercial sites​
• 6 trials supply novel products for patients outside theHarvard system in addition to internal patients

Investigational Products Manufactured by CMCF for Oncology Clinical Trials

Autologous Chimeric Antigen Receptor T Cells – 2024

• 19-253/23-281 Myeloma/AML – DFCI/MGH (Arcellx) “Universal” CAR
• 23-086 Lymphoma – DFCI (Oncternal) ROR-1 CAR
• 20-518 Myeloma – MGH (Maus)  Trimeric APRIL
• 20-532 Glioblastoma – MGH (Maus) EGFR CAR secreting T-cell Engaging Antibody Molecule
• 23-474 Lymphoma – MGH (Maus) CD79b-19 Bi-specific CAR
• 24-392 Neuroblastoma - BCH (Chiarle/Baumeister) ALK CAR-T

Cytokine-Induced Memory-Like NK Cells  - 2024

• 19-265, 23-534, 23-535  AML/MDS post, pre and with allo-HSCT – DFCI (Romee)
• 20-120 Myeloma - DFCI (Biohaven) CIML after auto HSCT
• 23-493 Ovarian – DFCI (Romee) Auto CIML (IP) +IL-2
• 23-688 RCC – DFCI (Romee) Auto CIML + IL-2

2025/2026 (in different phases of development)

CAR-T

• Majzner/Baumeister– BCH: B7H3 CAR T GBM
• Majzner – BCH: GD2 CAR-T NB/osteosarcoma
• Marasco/Wang DFCI: DFIR CAR T for RCC

Expanded T-regs

• Kean/Prokop: BCH: EVE Treg for cGVHD

TILs

• Reardon DFCI: TILs (CD137 Miltenyi) GBM
• Reardon DFCI: Gene Edited TILs INV441 GBM
• Wu/Fritch NextVAX-DFCI anti-tumor personalized vaccines

CAR-NK

• CD70 CAR NK cells in AML - DFCI (Romee)
• Xu/Celdara Medical, CAR-NK for RCC

Investigational Products Manufactured by CMCF for Non-Oncology Clinical Trials

Upcoming (2025-2026)

• M.Poznansky/VIC – MGH- B cell ENR on Prodigy   / Gene edited B-cells for ALS
• D.Bauer / E.Esrick –BCH- BCL11A in Sickle (Cas-9): Pilot and Feasibility Trial: Hematopoietic Stem Cell BCL11A Enhancer Gene Editing for Severe β-Hemoglobinopathies)
• C. Duncan – BCH- A Phase 1/2 Study of Lineage Specific GATA1 Expression as a Gene Therapy Cure for Diamond-Blackfan Anemia (DBA)
• A. Goldstein / A. Burns -MGH - Hirschsprung Project to isolate and enrich ENS myenteric ganglia from human resected colon tissue for the generation of neurospheres for cell therapy.
• Tolerance Bio – Generation of Pro-T for ex-vivo thymic production​

2024 and onwards

• Williams - BCH: GM-HPC for SCID-X1
• Williams/NHLBI/CIRM: Phase II multi-center GM-HPC for sickle cell disease
• Prockop - BCH: Phase II multi-center HPC TCRαβ+/CD19+ depletion for SCID-X1
• McLean Neuroregeneration Institute/BWH:  autologous iPSC-derived dopaminergic neurons for Parkinson’s
• Autologous cultivated autologous limbal epithelial cell (CALEC)- Mass Eye & Ear Institute

Manufactured-Off-Site (MOS)

• 29 IEC Clinical Trials, 6 Licensed IEC products, 4 licensed gene therapy stem-cell products where products are manufactured off site (MOS)
• CMCF serves as the intermediary to maintain chain-of-identity (COI) and chain-of-custody (COC)
• Responsible for shipping, inventory, thaw and release for infusion
• Diseases treated include:
  • Licensed CARs -  B-ALL, B-NHL, Myeloma – DFCI
  • Licensed CARs -  B-ALL – DFCI Adult and Pedi
  • Licensed GT SCT - beta-Thalassemia, sickle cell disease, ALD – BCH and DFCI
  • Trials – B&T-ALL, AML, CNS, Myeloma, Smoldering MM, Breast, GI (Gastric, Colon, Anal, HCC), Head&Neck, Lung (SCLCa, NSCLCa), RCC, Sarcoma, Viral Diseases – DFCI, BCH    (Non-Onc Lupus, Rheumatoid Arthritis)
• Types of Cells Delivered: - Auto and Allo T-cell CARs, Allo NK CARs, Auto eTCRs, TAC cells, Anti-viral CTLs

Scientific & Operational Accomplishments

Innovation in Cell Manufacturing

• 7 Miltenyi CliniMACs Prodigies – manufacturing for pts enrolled across DF/HCC and other US sites.
• Provides automated closed system for cell-selection, activation, transduction, and cell expansion
• Multiple virus types, products and diseases
• Upcoming NK CARs and TILs and combination with electroporation
• Incorporating new cell-selection/purification technologies (Miltenyi Tyto, and in 2026, Cellular Highways 1 sorters)

L7 Enterprise Platform – Electronic Manufacturing Documentation

• Multi-year implementation plan in 4 major phases
• Currently in Phase 1c – building quality control tests and product release log
• Future expansion to product issue and instrument integration and processing documents addressed.

Development a Novel Gene Delivery Core (Vector Production Facility)

• Located on JFB 3

Notable examples of therapies and protocols CMCF currently supported are shown below:

CELLF-HELP Training and Inservice

The Dana-Farber Cancer Institute’s Cell Manipulation Core Facility (CMCF) is approved to provide clinical stem cell transplant services to all Harvard affiliated hospitals. As one of the largest stem cell processing centers in the world, the CMCF manufactures over 1000 products per year.

In the continuum of care for patients treated for cancer and nonmalignant disease, hematopoietic stem cell transplantation has been both the standard for clinical treatment and the basis for novel therapeutic advancements. Although effectual, stem cell transplantation poses many risks and potential complications to the recipient. It is extremely important to have a dedicated and well-trained team throughout the treatment course. In this circle of patient care, the stem cell transplant lab’s mission is to provide cell therapy products that are both safe and effective prior to infusion. Technical procedure times range from 30 minutes to 12 hours; below are examples of best practices used in Cell Manipulation Core Facility procedures.

Processing Fundamentals

Products are processed due to major and minor blood type incompatibility, presence of high titer antibody to donor red cells, and volume restrictions.

Product Types

Hematopoietic Progenitor Cells (HPCs): Stem cells that give rise to both the red and white cell lineages.

HPC, Apheresis: Donors are given growth factors or chemotherapy, releasing stem cells from the bone marrow into the peripheral blood for collection by apheresis. Benefits include higher cell yields and a less invasive procedure in comparison to harvested bone marrow.

HPC, Marrow: Stem cells, as well as other desirable cellular lineages are collected from the iliac crest or sternum via multiple needle aspirations. Marrow products are utilized for patients with conditions that do not benefit from the increased risk of Graft Versus Host Disease (GVHD) following HPC, Apheresis transplantation. Donors may also prefer this collection method if they are averse to taking growth factors.

HPC, Cord: Blood containing stem cells is collected from the umbilical cord and placenta. Although HPC-Cord products contain less cells then other sources, they are a more widely available option for people who cannot find well matched donors.

Therapeutic Cells, Apheresis: Leukocytes are collected from the peripheral blood by apheresis. These cells are used in donor lymphocyte infusions for the treatment or prevention of tumor relapse and infection.