Methods of preparing anti-human papillomavirus antigen T cells
Inventors
Hinrichs, Christian S. • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-11918640-B2
Publication Date
2024-03-05
Expiration Date
2034-07-14
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Abstract
Disclosed are methods of preparing an isolated population of human papillomavirus (HPV)-specific T cells comprise dividing an HPV-positive tumor sample into multiple fragments; separately culturing the multiple fragments; obtaining T cells from the cultured multiple fragments; testing the T cells for specific autologous HPV-positive tumor recognition; selecting the T cells that exhibit specific autologous HPV-positive tumor recognition; and expanding the number of selected T cells to produce a population of HPV-specific T cells for adoptive cell therapy. Related methods of treating or preventing cancer using the T cells are also disclosed.
Core Innovation
The invention provides methods of preparing an isolated population of human papillomavirus (HPV)-specific T cells by dividing an HPV-positive tumor sample into multiple fragments, separately culturing these fragments in the presence of cytokines (preferably only one cytokine such as interleukin-2), obtaining T cells from the cultured fragments, testing the T cells for specific autologous HPV-positive tumor recognition and/or HPV antigen recognition, selecting T cells exhibiting such recognition, and then expanding the selected T cells to produce a clinically useful HPV-specific T cell population for adoptive cell therapy.
The methods address an unmet need for additional treatments for cancers, particularly HPV-associated cancers, which often have poor prognosis despite advances like chemotherapy. The inventive methods may generate T cells that recognize HPV antigens E6 and E7, which are specifically and constitutively expressed by cancer cells but not by normal cells, enabling targeted destruction of cancer cells while potentially minimizing toxicity to normal cells.
Furthermore, the methods can include nonmyeloablative chemotherapy, making them suitable for patients ineligible for total body irradiation-based treatments, such as those with prior myeloablative therapy or certain comorbidities. The approach can be used to treat or prevent HPV-positive cancers unresponsive to chemotherapy, surgery, or radiation, generating HPV-specific T cells at a scale and grade suitable for clinical use.
Claims Coverage
The patent includes one independent claim directed to a population of HPV-specific T-cells produced by a specific method, detailing the core inventive steps related to preparation and expansion.
Preparation of HPV-specific T cells from fragmented HPV-positive tumor samples
The method involves dividing an HPV-positive tumor sample obtained from a patient into multiple fragments and culturing these fragments in the presence of at least one cytokine to obtain T-cells.
Expansion of T cells using feeder cells and stimulatory agents
Expanding the T cells using one or both of irradiated allogeneic feeder cells and irradiated autologous feeder cells, combined with one or both of OKT3 antibody and interleukin-2 (IL-2), without depleting CD4+ cells.
Production of a therapeutic TIL population suitable for treating HPV-positive cancers
The resulting expanded population comprises a therapeutic population of HPV-specific tumor infiltrating lymphocytes (TILs) suitable for administration to the patient to treat or prevent HPV-positive cancers including cervical cancer, head and neck squamous-cell carcinoma, and other specified cancers.
Characteristics of the expanded T cell population
The HPV-specific T-cells secrete at least about 200 pg/mL of interferon-γ, comprise T-cells exhibiting specific autologous HPV-positive tumor recognition and/or HPV antigen recognition, may include multiple T-cells with different HPV specificities, and recognize HPV 16 or HPV 18 positive cancer cells and antigens including E6 and E7.
Details of culturing and dividing steps
The culturing step may involve gas permeable containers and use of interleukin-2; dividing the tumor sample can be mechanical or enzymatic; the expansion occurs over about 10 to 14 days, possibly in gas permeable containers.
The claims cover the method of generating an expanded, therapeutically suitable population of HPV-specific T cells from HPV-positive tumor fragments involving specific culturing, selection, and expansion steps using defined cytokines, feeder cells, and stimulatory antibodies without depleting CD4+ cells, enabling treatment of various HPV-associated cancers.
Stated Advantages
The methods generate T cells from HPV-positive cancers at a clinical grade and scale suitable for use.
The T cells specifically recognize HPV antigens E6 and E7, targeting cancer cells while minimizing damage to normal cells, thereby reducing toxicity.
The methods allow treatment of patients ineligible for total body irradiation, such as those with prior myeloablative therapy or comorbidities, by using nonmyeloablative chemotherapy.
The methods can effectively treat or prevent HPV-positive cancers that are unresponsive to chemotherapy, surgery, or radiation.
Documented Applications
Preparation of populations of HPV-specific T cells for adoptive cell therapy in treating HPV-positive cancers.
Treatment or prevention of cancer in mammals, particularly HPV-positive cancers including cervical cancer, head and neck squamous-cell carcinoma, and other HPV-associated tumors.
Use of enriched CD8+ or CD4+ T cell populations for improved tumor recognition and clinical expansion.
Clinical administration of expanded HPV-specific T cells to patients following nonmyeloablative lymphodepleting chemotherapy.
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