Tumor infiltrating lymphocytes and methods of therapy
Inventors
Moriarity, Branden • Webber, Beau • Choudhry, Modassir • Rosenberg, Steven A. • Palmer, Douglas C. • Restifo, Nicholas P.
Assignees
Intima Bioscience Inc • University of Minnesota System • US Department of Health and Human Services
Publication Number
US-11154574-B2
Publication Date
2021-10-26
Expiration Date
2037-10-18
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Genetically modified compositions, such as non-viral vectors and tumor infiltrating lymphocytes, for the treatment of gastrointestinal cancer are disclosed. Disclosed are methods of utilizing a CRISPR system to generate genetically modified compositions. Also disclosed are the methods of making and using the genetically modified compositions for the treatment of gastrointestinal cancer.
Core Innovation
The invention discloses genetically modified compositions, including non-viral vectors and tumor infiltrating lymphocytes (TILs), for treating gastrointestinal cancer. It describes methods utilizing a CRISPR system to generate genetically modified compositions, particularly by disrupting at least a portion of the cytokine inducible SH2-containing protein (CISH) gene in TILs. The methods include preparative regimens with immunosuppressants, administration of antifungal agents, antibiotics, and immunostimulants, combined with infusion of the genetically modified TILs.
The problem addressed arises from the challenges faced in using TIL therapy for solid tumors other than metastatic melanoma, due to suppressive tumor microenvironment effects and intrinsic T-cell impairments. While immune-checkpoint inhibitors provide some relief, their systemic activity causes risks of autoimmune side effects. Genetic engineering of lymphocytes has been successful mostly in hematologic tumors but is limited in solid tumors due to lack of specific molecular targets. The invention aims to overcome these barriers by engineering TILs to disrupt the CISH gene, enhancing antitumor activity in gastrointestinal cancers.
Claims Coverage
The independent claims focus on methods of treating cancer by administering genetically modified lymphocytes with specific genomic modifications in the cytokine inducible SH2-containing protein gene, including associated preparative and adjunct therapies.
Genomic modification of lymphocytes targeting CISH gene
Administering to a subject human lymphocytes (T cells or NK cells) comprising a genomic modification (indel formation) in a target sequence of the CISH gene, specifically at a sequence comprising SEQ ID NO: 77, resulting in suppressed expression of the CISH protein.
Use of tumor infiltrating lymphocytes
The human lymphocytes administered can be tumor infiltrating lymphocytes (TILs), which may be autologous or allogeneic to the subject.
Treatment of gastrointestinal and other cancers
The method is applicable for treating gastrointestinal cancer, breast cancer, lymphoma, or prostate cancer.
Adjunct preparative and supportive therapies
The method may further comprise administering preparative regimens including immunosuppressants, and adjunct administration of antifungal agents, antibiotics, or immunostimulants to the subject.
Genome editing resulting in nucleotide insertion
The genomic modification may include a nucleotide insertion in the target sequence compared to an unmodified CISH gene.
The claims encompass methods of treating cancers, especially gastrointestinal cancer, by administering genetically modified lymphocytes with disrupted CISH gene sequences using CRISPR, together with preparative immunosuppression and supportive anti-infective therapies, highlighting use of TILs with enhanced antitumor properties.
Stated Advantages
Enhanced expansion, functional avidity, and cytokine polyfunctionality of tumor-specific CD8+ T cells resulting in pronounced and durable regression of tumors.
Genetic deletion of CISH in tumor-specific T cells increases infiltration into antigen-relevant tumors while maintaining cell viability and proliferation after CRISPR modification.
Use of CRISPR-mediated genomic editing in TILs offers a high efficiency, specific, and safe engineering approach with minimal off-target effects.
The method allows scale-up to therapeutic doses consistent with good manufacturing practice (GMP) standards, supporting clinical application.
Documented Applications
Treatment of refractory metastatic cancers, including gastrointestinal cancer, by adoptive cell transfer of TILs genetically modified to disrupt the CISH gene.
Using CRISPR technology to knockout checkpoint genes like CISH to enhance anti-tumor activity of TILs in adoptive cell therapies.
Combination therapy involving preparative lymphodepleting regimens (cyclophosphamide and fludarabine), administration of antifungal agents (e.g., fluconazole), antibiotics (e.g., trimethoprim-sulfamethoxazole), and immunostimulants (e.g., aldesleukin) alongside genetically engineered TIL infusion.
Clinical trials for gastrointestinal cancer patients involving whole-exome sequencing of tumor to identify mutations, isolating mutation-reactive TILs, CRISPR editing of CISH gene, expansion and infusion for cancer immunotherapy.
Interested in licensing this patent?