Adoptive cell therapy with young T cells
Inventors
Dudley, Mark E. • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-9074185-B2
Publication Date
2015-07-07
Expiration Date
2030-08-26
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Abstract
The invention provides a method of promoting regression of a cancer in a mammal comprising (i) culturing autologous T cells; (ii) expanding the cultured T cells; (iii) administering to the mammal nonmyeloablative lymphodepleting chemotherapy; and (iv) after administering nonmyeloablative lymphodepleting chemotherapy, administering to the mammal the expanded T cells, wherein the T cells administered to the mammal are about 19 to about 35 days old and have not been screened for specific tumor reactivity, whereupon the regression of the cancer in the mammal is promoted.
Core Innovation
The invention provides a method of promoting regression of cancer in a mammal by culturing autologous T cells, expanding them, administering nonmyeloablative lymphodepleting chemotherapy, and then administering the expanded T cells to the mammal. The T cells administered are about 19 to about 35 days old, have not been screened for specific tumor reactivity, and promote cancer regression. The T cells are enriched for CD8+ T cells prior to expansion using OKT3 antibody, IL-2, and feeder lymphocytes, and the methods can involve cells about 19 to about 29 days old or about 19 to about 26 days old.
The background identifies that adoptive cell therapy (ACT) using tumor-reactive T cells after lymphodepletion can lead to durable responses in cancer patients, but traditional methods require extended in vitro culturing and individualized tumor reactivity screening, leading to technical, regulatory, and logistic challenges. The invention addresses the need for improved methods of treating cancer using ACT that simplify and shorten the process.
The methods advantageously provide T cells with improved in vivo proliferation, survival, and antitumor activity compared to older (about 44 days) T cells. The use of nonmyeloablative chemotherapy permits treatment of patients ineligible for total body irradiation regimens. The shortened culture period (about 19 to about 35 days) allows more patients to be treated before disease progresses. Not requiring in vitro screening for tumor reactivity reduces time, cost, and labor. Pooling bulk cultures instead of microcultures provides a diverse tumor reactivity repertoire. The young T cells have higher CD27 and CD28 expression, a longer telomere length, and a greater diversity of cells including CD4+ T cells, which are associated with better proliferation and antitumor effects.
Claims Coverage
The claims include one independent claim with multiple inventive features directed to the method of generating a T cell infusion product for treating cancer.
Culturing and enriching T cells
Culturing autologous T cells and enriching the cultured T cells for CD8+ T cells before expansion.
Rapid expansion to young T cells
Expanding the cultured T cells using OKT3 antibody, IL-2, and feeder lymphocytes to obtain an expanded number of T cells that are about 19 to about 35 days old.
Use without tumor reactivity screening
Providing the expanded T cells as a cell infusion product without prior screening for specific tumor reactivity, where the T cells recognize an antigen of cancer.
Higher expression of costimulatory molecules
Producing T cells having higher expression of CD27 and/or CD28 compared to T cells about 44 days old.
Longer telomere length
Producing T cells having a mean telomere length longer than T cells about 44 days old.
Higher frequency of CD4+ cells
Producing T cells having a higher frequency of CD4+ cells compared to T cells about 44 days old.
Narrower age ranges of T cells
Providing expanded T cells that are about 19 to about 26 days, about 19 to about 29 days, or about 23 to about 29 days old.
Modification of T cells for growth or specificity
Modifying the T cells to express a T-cell growth factor that promotes their growth and activation, or modifying T cells to express a T cell receptor with antigenic specificity for a cancer antigen.
The claims cover a method focused on culturing and enriching autologous T cells for CD8+, rapidly expanding young T cells to about 19 to 35 days old without tumor reactivity screening, and optionally modifying these T cells for enhanced growth or antigen specificity, with additional features related to improved expression markers and telomere length that contribute to antitumor efficacy.
Stated Advantages
T cells aged about 19 to 35 days provide improved in vivo proliferation, survival, and antitumor activity compared to older T cells.
Nonmyeloablative chemotherapy allows treatment of patients ineligible for more intensive regimens like total body irradiation.
Shortens the time to generate T cells for therapy from approximately 44 days to around 19 to 35 days.
Avoidance of in vitro screening for tumor reactivity reduces time, expense, and labor.
Pooling bulk cultures rather than microcultures preserves a more diverse range of tumor reactivities.
Young T cells have longer telomeres and higher expression of CD27 and CD28 costimulatory molecules, correlating with better clinical response and persistence.
The method is simpler and potentially automatable, facilitating wider adoption of adoptive cell therapy.
Documented Applications
Treatment of metastatic melanoma in human patients using adoptive cell therapy with young, CD8+ enriched T cells following nonmyeloablative lymphodepleting chemotherapy and IL-2 administration.
Use in treating cancers including but not limited to acute lymphocytic cancer, leukemia, rhabdomyosarcoma, bone, brain, breast, anal, eye, bile duct, neck, gallbladder, ovarian, prostate, skin, thyroid, and other listed cancers as explicitly described in the document.
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