T cell receptors recognizing mutated p53
A cell-receptor, specific technology for the treatment or prevention of cancer in mammals to address the limited options for cancer treatment, the unmet need for additional cancer treatments, and poor cancer prognosis
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Embodiment 1
[0167] This example demonstrates the isolation and specific reactivity of 4 TCRs against mutated p53 from patient 4127.
[0168] combine Figure 1-7 Experiments were performed on patient 4127 as described in , 36 and 37A-37C. Mutant p53-reactive T cells in this patient were identified by the methods described in US Patent Application No. 2017 / 0224800 ("Tran Method"). The method for isolating individual TCRs is described below.
[0169] use figure 1 One of the TCRs shown in transduced autologous PBLs and tested 2 weeks later. Autologous DC cells were plated at 3 x 10 4 Cells / well were plated and pulsed overnight with decreasing concentrations of WT p53-G245 peptide (wt) or mutant p53-G245S peptide (mut). Add 3x 10 per hole 4 Transduced T cells were co-cultured overnight at 37°C. The supernatant was harvested for IFN-γ ELISA. IFN-γELISA results see figure 1 . 4-1BB expression by FACS gating: lymphocytes\PI(neg)CD3 + \CD3 + MTCR + \CD8(neg)CD4 + . For FACS results ...
Embodiment 2
[0233]This example demonstrates the isolation and specific reactivity of 3 anti-mutant p53 TCRs from patient 4196.
[0234] Experiments were performed on Patient 4196 as described in Figures 8-11. The patient's p53-reactive T cells were identified by the Tran method as described in US Patent Application No. 2017 / 0224800. Individual TCRs were isolated using the Fluidigm method. The statistics of patient 4196 are shown in Table D.
[0235] Characterization of p53-responsive cells: the challenge of identifying the minimal epitope: The first predicted peptide with the mutated amino acid p53 R 175H is shown in Table C.
[0236] Form C
[0237] HLA HLA-A0201 Peptide HMTEVVRHC (SEQ ID NO: 530) core HMTEVVRHC (SEQ ID NO: 530) Affinity (nM) 7826.06 %grade 13.00
[0238] MG1 vs 4196-Rx1 TIL:COS7 cells were transfected with plasmids for TMG1 and HLA alleles. Cells were co-cultured with 4196Rx1 TIL infusion bags for 20 hours (h). see the res...
Embodiment 3
[0270] This example demonstrates the isolation of 11 anti-mutant p53 TCRs from patient 4238.
[0271] as for Figure 12-15 The experiment was performed on patient 4238 as described.
[0272] TIL fragments from patient 4238 (F1-F24, n=24) were co-cultured with TMG electroporated autologous APCs consisting of unrelated or mutated p53 sequences. Co-cultures were grown overnight at 37°C. IFN-γ secretion was assessed using the ELISPOT assay. see the results Figure 12 . Expression of 4-1BB was assessed by flow cytometry after gating on lymphocytes→live cells (PI negative)→CD3+ (T cells). see the results Figure 14 .
[0273]TIL fragments of patient 4238 (F1-F24, n=24) were co-cultured with autologous APCs pulsed with peptide vehicle (DMSO) or with a purified 25 amino acid peptide consisting of the mutant p53-R248Q sequence (HPLC method >95%) pulsed. Co-cultures were grown overnight at 37°C. IFN-γ secretion was assessed using the ELISPOT assay. see the results Figure 13...
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