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@ARTICLE{Onyshchenko:284400,
      author       = {K. Onyshchenko$^*$ and R. Luo and E. Firat and G.
                      Niedermann$^*$},
      title        = {{IL}-2/α{IL}-2 {C}omplexes {M}assively {E}xpand {S}ystemic
                      {T}umor-{S}pecific {T} {C}ells and {E}nhance {A}bscopal
                      {R}esponses to {R}adiation and α{PD}-1.},
      journal      = {International journal of radiation oncology, biology,
                      physics},
      volume       = {117},
      number       = {2S},
      issn         = {0360-3016},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2023-01989},
      pages        = {S73},
      year         = {2023},
      abstract     = {Early clinical trials have provided evidence for RT-induced
                      systemic effects in conjunction with αPD1 or IL-2 in
                      metastatic patients, but strong abscopal responses are
                      clinically rare. We investigated the effect of a triple
                      combination of CD122-directed IL-2/αIL-2 complexes (IL-2c),
                      hRT, and αPD1 on tumor-specific CD8+ T cell differentiation
                      and the abscopal effect vs. the respective dual
                      treatments.Mice bearing bilateral tumors were treated with
                      two fractions of 8 Gy (C51 colon carcinoma model) or 12 Gy
                      (B16 melanoma model); αPD1 was given weekly; IL-2c was
                      given for five consecutive days. Dependence of the
                      therapeutic effect on CD8+ T cells and T cells expressing
                      the chemokine receptor CXCR3 was assessed using depleting or
                      blocking antibodies. Differentiation stages of
                      tumor-specific CD8+ T cells in various compartments were
                      determined flow cytometrically using MHC-I tetramers and
                      appropriate antibodies. Anti-tumoral effects of
                      blood-derived and tumor-derived T cells were assessed in
                      adoptive T cell transfer experiments.The abscopal effect was
                      significantly stronger in triple-treated mice compared to
                      mice treated with RT/αPD1 (C51 model: p < 0.01; B16 model:
                      p < 0.05), RT/IL-2c (C51 model: p < 0.01; B16 model: p <
                      0.001) or αPD1/IL-2c (C51 model: p < 0.0001, B16 model: p <
                      0.01). Triple therapy improved survival and resulted in
                      complete cures of 3/12 mice in the C51 model and 2/12 mice
                      in the B16 model. These anti-tumor effects were associated
                      with dramatic expansion of tumor-specific CD8+ T cells.
                      Undifferentiated stem-like (TCF1+TIM3-PD1+) and
                      effector-like (CD101-TIM3+TCF1-PD1+) but not terminally
                      differentiated (CD101+TIM3+TCF1-PD1+) exhausted cells
                      particularly strongly increased. Moreover, IL-2c induced
                      CXCR3 mainly on non-terminally differentiated CD8+ T cells.
                      Both CD8+ (C51 model: p < 0.0001; B16 model: p < 0.01) and
                      CXCR3+ (C51 model: p < 0.0001) T cells were crucial for the
                      RT-induced abscopal effect upon RT/αPD1/IL-2c treatment.
                      Finally, we found that peripheral blood from triple-treated
                      mice is an effective source of T cells for adoptive T cell
                      transfer.RT/αPD1/IL-2c triple treatment resulted in
                      superior local and systemic expansion of tumor-specific CD8+
                      T cells with stem- and effector-like phenotypes. Also, IL-2c
                      strongly increased CXCR3+CD8+ T cells that were associated
                      with pronounced abscopal responses in models with an
                      established metastasis resistant to αPD1/IL-2c and only
                      transiently responding to RT/αPD1 or RT/IL-2c. Therefore,
                      such triple combinations appear promising for clinical
                      evaluation in metastatic patients.},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37784564},
      doi          = {10.1016/j.ijrobp.2023.06.383},
      url          = {https://inrepo02.dkfz.de/record/284400},
}