Adoptive Cell Therapy of Autologous T cell Receptor-Engineered T Cells Targeting the p53 Neoantigens in Human Solid Tumors

Adoptive T cell therapy (ACT) using T cell receptor (TCR)-engineered T cells can mediate regression of advanced human cancers. How TCR-transduced T cells change post-ACT in vivo is currently not well understood. We screened 78 patients for TP53 mutations by whole exome sequencing and whole transcriptome sequencing. Of the 78 patient samples, 49 patient samples were previously reported (phs001003) and 2 additional patients were reported in phs002735. In this accession we report the sequencing data of remaining 23 patients and include 6 additional samples from previously published patients. Additionally, we treated a patient with chemo-refractory breast cancer that expressed mutant p53 R175H with autologous T cells transduced with an allogeneic TCR targeting p53 R175H with human leukocyte antigen (HLA) restriction of A*02. The patient had a partial response for 6 months with 55% tumor regression. The T cells from the infusion product and the peripheral blood T cells at 6 weeks post-ACT were analyzed using 10X single cell transcriptome analysis.]]>
Inclusion CriteriaAge greater than or equal to 18 years and less than or equal to 70 years Metastatic solid cancer with at least one lesion that can be measured.Metastatic solid cancer falls into one of five cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); (4) endocrine tumors including neuroendocrine tumors, and (5) multiple myeloma with solid masses (plasmacytomas).
Evaluable solid cancer that has recurred following standard chemotherapy or standard systemic therapy
-Normal basic laboratory values.No allergies or hypersensitivity to high-dose aldesleukin administration No concurrent major medical illnesses or any form of immunodeficiency.
Exclusion CriteriaWomen of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
Concurrent systemic steroid therapy.
Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Participants who have decreased immune-competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
History of coronary revascularization or ischemic symptoms.
For select participants with a clinical history prompting cardiac evaluation: last known left ventricular ejection fraction (LVEF) less than or equal to 45%.
For select participants with a clinical history prompting pulmonary evaluation: known forced expiratory volume in the first second (FEV1) less than or equal to 50% predicted.
Participants who are receiving any other investigational agents. ]]>
The Surgery Branch at National Cancer Institute (NCI) has been developing an adoptive T cell therapies. Given the high frequency of TP53 mutations, Kim et al. focused on determining the immunogenicity of TP53. By doing neoantigen screening, Kim et al. identified tumor-reactive tumor infiltrating lymphocytes and a number of TCRs that could target TP53 mutations. Finally, one patient with metastatic breast cancer received a TCR-engineered autologous T cell therapy and showed a clinical response.]]>