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-8383099-B2
Publication Date
2013-02-26
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 a cancer in a mammal by culturing autologous T cells, expanding the cultured T cells using OKT3 antibody, IL-2, and feeder lymphocytes with enrichment for CD8+ T cells prior to expansion, administering nonmyeloablative lymphodepleting chemotherapy to the mammal, and following chemotherapy by administering the expanded T cells. The T cells administered are about 19 to about 35 days old and have not been screened for specific tumor reactivity, promoting cancer regression.
The problem addressed is that adoptive cell therapy using tumor reactive T-cells requires sophisticated processing and extended in vitro culturing, leading to technical, regulatory, and logistic challenges for biological therapy. There is a need for improved methods for treating cancer using adoptive cell therapy that are simpler and faster, reducing time, expense, and labor and expanding patient eligibility.
The invention provides advantages including the use of younger T cells (about 19 to 35 days old) which exhibit improved in vivo proliferation, survival, and antitumor activity compared to older cells. The nonmyeloablative chemotherapy used allows treatment of patients who are ineligible for total body irradiation. The time required to generate T cells is reduced, permitting treatment before disease progression. The method removes the need for specific tumor reactivity screening, enabling administration of pooled bulk cultures that provide a diverse repertoire of tumor reactivities. Young T cells also contain a higher frequency of CD4+ cells, express higher levels of co-stimulatory molecules (CD27 and CD28), and have longer telomeres, which are associated with better therapeutic responses and persistence.
Claims Coverage
The patent includes two independent claims, both directed to methods of promoting cancer regression in mammals by culturing, expanding, and administering young T cells following nonmyeloablative lymphodepleting chemotherapy.
Administration of young T cells without prior tumor reactivity screening
The method includes administering to a mammal T cells that are about 19 to about 35 days old that have been cultured and expanded with OKT3 antibody, IL-2, and feeder lymphocytes, enriched for CD8+ cells, after nonmyeloablative lymphodepleting chemotherapy, without screening for specific tumor reactivity, to promote regression of cancer.
Use of nonmyeloablative lymphodepleting chemotherapy with adoptive T cell transfer
The method employs nonmyeloablative lymphodepleting chemotherapy, comprising administration of cyclophosphamide and fludarabine (around 60 mg/kg cyclophosphamide for two days and 25 mg/m2 fludarabine for five days), prior to administration of young expanded T cells to the mammal.
CD8+ T cell enrichment before expansion
The cultured T cells are enriched for CD8+ T cells prior to rapid expansion, reducing CD4+ cells and potentially improving anti-tumor responses and clinical outcomes.
Administration of T-cell growth factors
The method includes either modifying autologous T cells to express T-cell growth factors (e.g., IL-2, IL-7, IL-15, IL-12), or administering such T-cell growth factors concomitantly or subsequently to T-cell administration, thereby promoting T-cell growth and activation.
Administration of a therapeutically effective T-cell dose
From about 1.0×1010 to about 13.7×1010 T cells are administered, preferably around 5.0×1010, intravenously.
Application to melanoma and metastatic cancer
The method is applicable to treating melanoma, including metastatic melanoma, with T cells that recognize melanoma antigens such as MART-1.
Use of young T cells with enhanced features
Administered T cells have higher expression of CD27, CD28, higher frequency of CD4+ cells, and longer telomere lengths compared to older T cells (about 44 days old), which correlates with improved persistence and antitumor activity.
Administration of T cells with or without engineered antigen specificity
T cells may be modified to express T cell receptors with antigenic specificity for cancer antigens prior to administration.
Use of T cells about 19 to about 29 days old
An alternative method administers cultured and expanded T cells about 19 to 29 days old, enriched for CD8+ cells, following nonmyeloablative lymphodepleting chemotherapy, without screening for tumor reactivity, to promote cancer regression.
The claims cover methods of promoting cancer regression by administering young (approximately 19-35 days old) autologous CD8+ enriched T cells expanded with specific stimuli following nonmyeloablative lymphodepleting chemotherapy, without requiring prior tumor reactivity screening, optionally combined with T-cell growth factor administration. The method includes treatment of melanoma and employs specific conditioning regimens and T-cell characteristics linked to improved therapeutic outcomes.
Stated Advantages
Young T cells (about 19-35 days old) provide improved in vivo proliferation, survival, and antitumor activity compared to older T cells.
Nonmyeloablative lymphodepleting chemotherapy enables treatment of patients ineligible for total body irradiation, such as those who underwent prior myeloablative therapies or have comorbid conditions.
The reduced time required to generate T cells expands patient eligibility by allowing treatment before disease progression.
Eliminating prior screening for specific tumor reactivity reduces time, expense, and labor, and allows administration of pooled bulk cultures with diverse tumor reactivities.
Young T cells exhibit higher expression of co-stimulatory molecules CD27 and CD28 and longer telomeres, associated with better persistence and clinical responses.
CD8+ enrichment reduces CD4+ regulatory T cells, potentially enhancing antitumor activity and reducing cytokine-associated toxicities.
The method is simpler and faster, facilitating more widespread use of adoptive cell therapy.
Documented Applications
Treatment of melanoma, including metastatic melanoma, using adoptive cell therapy with autologous T cells.
Treatment of various cancers including, but not limited to, acute lymphocytic cancer, acute myeloid leukemia, bone cancer, brain cancer, breast cancer, cervical cancer, glioma, Hodgkin lymphoma, kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma, multiple myeloma, non-Hodgkin lymphoma, ovarian cancer, prostate cancer, skin cancer, testicular cancer, thyroid cancer, urinary bladder cancer, and digestive tract cancers.
Treatment of cancer in mammals, especially humans, wherein the adoptive T cell therapy promotes regression of cancer following nonmyeloablative lymphodepleting chemotherapy and infusion of young T cells.
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