CCR Center for Cell-based Therapy
The ability of cancer cells to move and spread depends on actin-rich core structures such as the podosomes (yellow) shown here in melanoma cells. Cell nuclei (blue), actin (red), and an actin regulator (green) are also shown.
Credit: Julio C. Valencia, NCI, NIH
Cell-based therapies have long been a critical part of modern medicine. This includes use in blood transfusions, skin grafts, as well as transplantation of organs and bone-marrow. The potential therapeutic properties of ‘living cells as specific drugs’ in the treatment of cancer has more recently become clear. Recent advances at the NCI’s Center for Cancer Research (CCR) have shown that:
- Naturally-occurring T cells can trigger objective responses in patients with melanoma, colon cancer, breast cancer, cholangiocarcinoma and others.
- Gene-engineered T cells can cause regressions in patients with leukemia, lymphoma, melanoma and sarcoma.
An important goal is to adapt this approach for successful treatment of a variety of cancer types, including commonly occurring epithelial cancers such as carcinoma of the breast, lung, prostate and colon. This would bring this new and promising treatment to hundreds of thousands more patients each year. The CCR Center for Cell-based Therapy (CCT) was formed to accelerate this process.
The mission of the Center for Cell-based Therapy is to facilitate the discovery and development of cellular immunotherapies for patients with cancer
The CCR has long been a leader in developing cell-based treatments for cancer. The CCT aims to:
- Build on the CCR’s existing strengths in cell-based therapy
- Fortify natural synergies between existing collaborators and bring together NIH-wide expertise in immunology, gene therapy, gene editing and regenerative medicine.
- Create outstanding infrastructure to more rapidly advance cell-based immunotherapies
Dr. Steven A. Rosenberg speaking with a patient at the NIH Clinical Center.
A pseudo-colored scanning electron micrograph of cancer cells (white) being attacked by two cytotoxic T cells (red).
Credit: Rita Elena Serda, Duncan Comprehensive Cancer Center at Baylor College of Medicine.
Specifically, the CCT seeks to:
- Build a Solid Foundation: By developing the principles of cell based therapies through strong basic research.
- Accelerate Translational Work: By enhancing the ability of basic research laboratories to translate their work into preclinical and clinical studies
- Facilitate Innovation: By taking early stage research and bringing it to the clinic.
- Teach and Train: By hosting visiting investigators and holding educational symposia.
- Share and Provide Access to Technology: By creating robust technology transfer to non-for-profit and to commercial entities.
- Create a vision for the Future: By exploring new directions for the use of ‘cells as drugs.’
The CCT is part of the CCR, which is the largest division in the NCI intramural research program. Located on the Bethesda campus of the NIH, this is an ideal site for leading the emerging field of cell-based therapies. Advantages include:
- Broad expertise in the basic science of cell-based techniques.
- A world-class community of immunologists in the CCR, NCI and NIH with expertise spanning basic, translational and clinical research
- Access to the NIH Clinical Center, the Nation’s largest research hospital which is staffed with experienced teams of experimental clinicians.
- Unique patient populations for whom existing therapies have been insufficient.
- Established infrastructure for interacting with regulatory agencies in the absence of financial conflicts-of-interest.
- New efforts to increase the capacity for pre-clinical and clinical production of human cells. This includes a large GMP-quality cell production laboratory with cell sorting, as well as the capacity for GMP vector production and new space for completing at or near scale experimental pre-clinical work (eg CRISPR, iPSC).
Scanning electron micrograph of a T lymphocyte, such as those used at the CCR to kill tumors in an approach known as adoptive T-cell immunotherapy.
Credit: NIAID, NIH
T cells surround and attack a cancer cell. CAR-T cells, first developed at the CCR, are made by inserting receptors into T cells and have been used to successfully treat some blood cancers.
Credit: Alex Ritter, Jennifer Lippincott Schwartz and Gillian Griffiths, NIH
In addition to maintaining long-standing collaborations, the CCT will capitalize on the considerable strength of the immunology community in the CCR, the NCI and the NIH through interaction with groups such as the:
- CCR Center of Excellence in Immunology
- NIH Immunology Interest Group
- Center for Human Immunology
- Cytokine Interest Group
If you would like more information on the Center for Cell-based Therapy please contact Dr. Nick Restifo for more information.
Working List of GMP Vectors
GMP Vectors Produced at the Surgery Branch, CCR
- MART-1 - TCR (DMF5 - HLA-A2-restricted); shared with University of Montreal, UCLA
- CD19 (CAR); Shared with Ped Onc Branch, CCR; Ella Institute, Israel
- VEGF-R2 (CAR)
- IL-12 (Cytokine)
- MAGE-A3 TCR (A2-restricted) Shared with Massachusetts Gen Hospital (MCB)
- Mesothelin (CAR)
- EGFRvIII (CAR); Shared with Duke
- murine NY-ESO-1 TCR; Shared with Albert Einstein
- MAGE-A3; TCR (DP4-restricted)
- Thyroglobulin; TCR
- HPV E6 (TCR); Shared with ETIB, CCR
- BCMA (CAR); Shared with ETIB
- CD27-41BB-Zeta (CAR)
- 2G1 (DR4/Trail) (TCR)
- CEA (TCR)
- HPV E7 (TCR) ETIB, CCR
- MAGE-A3 (TCR) (A-1-restricted)
- KRAS-G12V (TCR)
Scanning electron microscope image of dendritic cells (green), interacting with T cells, (pink).
Credit: Victor Segura Ibarra and Rita Serda, Ph.D., NCI, NIH.
A Vision for the Future
Cell-based therapies have been successful in treating some patients with metastatic melanoma, as well as certain types of lymphomas and leukemias. There are also promising preliminary results treating patients with colon cancer, breast cancer and cholangiocarcinoma. The foundation for developing treatments for the most commonly occurring cancers has been created and the work is ongoing.
We seek to develop highly personalized cell-based treatments that target individual mutations within a patient’s tumors. This will give new hope to the hundreds of thousands of patients with many types of cancer.
Dr. Steven A. Rosenberg with a patient at the NIH Clinical Center.
An additional long-term goal is to facilitate inter-institute collaborations to develop cell-based treatments for other disorders, diseases and injuries such as:
- Infectious diseases (eg HIV/AIDS)
- Monogenic disorders (eg Hemophilia, Sickle-cell anemia).
- Autoimmunity (eg. Diabetes)
- Spinal Cord Injury and Neurological Diseases (eg. Parkinson’s disease)
If you would like more information on the Center for Cell-based Therapy please contact Dr. Nick Restifo for more information.
Selected Publications in Cell-based Therapy
- Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, and White DE. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987; 316(15): 889-97.
- Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA, Simpson C, Carter C, Bock S, Schwartzentruber D, Wei JP, White DE. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988; 319(25): 1676-80.
- Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, Karson EM, Lotze MT, Yang JC, Topalian SL, Merino MJ, Culver K, Miller DA, Blaese MR, Anderson WF. Gene transfer into humans--immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990; 323(9): 570-8.
- Restifo NP, Esquivel F, Kawakami Y, Yewdell JW, Mulé JJ, Rosenberg SA and Bennink JR. Identification of human cancers deficient in antigen processing. J Exp Med, 1993; 177(2): 265-272.
- Mackall, C. M., Fleischer, T., Brown, M., Mag rath, I., Wexler, L., Horowitz, M., Andrich, M., Chen, C., Feurstein, I., and Gress, R.E., Age, thymopoiesis, and CD4+ T lymphocyte regeneration following chemotherapy. N Engl J Med. 1995; 332: 143-149.
- Bronte V, Chappell D, Apolloni, Cabrelle A, Wang M, Hwu P and Restifo NP. Unopposed production of granulocyte macrophage colony stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen presenting cell maturation. J Immunol, 1999; 162(10): 5728 5737.
- Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002; 298(5594): 850-4.
- Hanada, K., Yewdell, J.W., Yang, J.C. Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature. 2004; 427: 252-256.
- L Gattinoni, SE Finkelstein, CA Klebanoff, PA Antony, DC Palmer, PJ Spiess, LN Hwang, Z Yu, C Wrzesinski, DM Heimann, CD Surh, SA Rosenberg and NP Restifo. Removal of homeostatic cytokine sinks by lymphodepletion enhances autoimmunity and the effectiveness of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005: 202(7); 907-12.
- Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006; 314(5796), 126-9.
- Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010; 116(19): 3875-86.
- Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010; 116: 4099-102.
- Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012; 119(12): 2709-20
- Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011; 17(13): 4550-7.
- L Gattinoni, E Lugli, Y Ji, Z Pos, CM Paulos, MF Quigley, JR Almeida, E Gostick, Z Yu, C Carpenito, E Wang, DC Douek, DA Price, CH June, FM Marincola, M Roederer and NP Restifo. A human memory T cell subset with stem cell-like properties. Nat Med. 2011; 17(10): 1290-7.
- Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011; 29(7): 917-24.
- Kochenderfer, J.N., Dudley, M.E., Carpenter, R.O., Kassim, S.H., Rose, J.J., Telford, W.G., Hakim, F.T., Halverson, D.C., Fowler, D.H., Hardy, N.M., Mato, A.R., Hickstein, D.D., Gea-Banacloche, J.C., Pavletic, S.Z., Sportes, C., Maric, I., Feldman, S.A., Hansen, B.G., Wilder, J.S., Black-Lock Schuver, B., Jena, B., Bishop, M.R., Gress, R.E*., and Rosenberg, S.A*. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013; 122: 4129-4139.
- Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, Parkhurst MR, Yang JC, Rosenberg SA. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014; 344 (6184): 641-645
- Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, Raffeld M, Feldman S, Lu L, Li YF, Ngo LT, Goy A, Feldman T, Spaner DE, Wang ML, Chen CC, Kranick SM, Nath A, Nathan DA, Morton KE, Toomey MA, Rosenberg SA. Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies. J Clin Onc. 2015; 33(6): 540-9
- S. Stevanović, L. M. Draper, M. M. Langhan, T. E. Campbell, M. L. Kwong, J. R. Wunderlich, M. E. Dudley, J. C. Yang, R. M. Sherry, U. S. Kammula, N. P. Restifo, S. A. Rosenberg, C. S. Hinrichs, Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells, J. Clin. Oncol. 2015; 33: 1543–1550.
- Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, Gartner JJ, Zheng Z, Li YF, Ray S, Wunderlich JR, Somerville RP, Rosenberg SA. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015; 350(6266): 1387-90.
- Wang QJ, Yu Z, Griffith K, Hanada K, Restifo NP, Yang JC. Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. Cancer Immunol Res. 2016; 4: 204-14.
- Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, Kriley IR, Rosenberg SA. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016; 375(23): 2255-2262
- Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH, Palmer DC, Phan AT, Goulding J, Gattinoni L, Goldrath AW, Belkaid Y, Restifo NP. Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche. Cell. 2016; 166(5): 1117-1131.
- Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Linehan WM, Roychoudhuri R, Restifo NP. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature. 2016; 537(7621):539-543
- Stevanović S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, Robins HS, Robbins PF, Klebanoff CA, Rosenberg SA, Hinrichs CS. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017; 356(6334):200-205
- Patel SJ, Sanjana NE, Kishton RJ, Eidizadeh A, Vodnala SK, Cam M, Gartner JJ, Jia L, Steinberg SM, Yamamoto T, Merchant A, Mehta GU, Chichura A, Shalem O, TranE, EilR, Sukumar M, Guijarro EP, Day CP, Robbins P, Feldman S, Merlino G, Zhang F, Restifo NP. Identification of essential genes for cancer immunotherapy. Nature. 2017. 548; (7669): 537-542
- Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy. Kochenderfer JN, Somerville RPT, Lu T, Yang JC, Sherry RM, Feldman SA, McIntyre L, Bot A, Rossi J, Lam N, Rosenberg SA. Mol Ther. 2017 Oct 4;25(10):2245-2253