IMAGING IMMUNITY – from Nanoscale to Macroscale | Insights from Biophysics
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Invited Lecture | Angela Krackhardt, Munich

Session chair: Katrien Vandoorne (Eindhoven, Netherlands)
 
Date: Tuesday, 14 January, 2020, 8:45 AM - 9:30 AM

Contents

8:45 AM -01

Development of personalized treatment and novel monitoring approaches for T-cell based immunotherapies in cancer (#49)

Angela M. Krackhardt1

1 TU München, Klinikum rechts der Isar, 3rd Medical Department, München, Bavaria, Germany

Content

Cancer immunotherapy has shown high efficacy in the treatment of diverse malignant diseases. Especially immune checkpoint modulation by antibodies have greatly advanced the field and demonstrated that patients` own T cells can detect and reject tumor cells. The characterization of T-cell responses in the context of anti-tumor immune responses is highly essential to understand success and failure of current treatment strategies. For those patients who cannot build an own anti-tumor immune response, redirection of T cells by tumor-reactive T-cell receptors (TCR) represents an highly attractive alternative therapeutic approach. We have recently developed novel algorithms to identify tumor-associated and tumor-specific target antigens on tumors and defined characteristics important for effective tumor rejection. (1) We have defined characteristics of MHC-mismatched tumor-reactive TCR and respective targeted tumor-associated antigens essential for tumor rejection in a transplant-associated settting of adoptive T-cell transfer. (2) We have shown that direct identification of tumor-specific neoantigens derived from somatic mutations of patients` tumor samples is feasible by a combined mass spectrometry (MS)/next generation sequencing approach (Bassani-Sternberg et al., Nature Communications 2016). We have additionally identified and characterized a number of TCR targeting diverse neoantigens with respect to their spatial and temporal location as well well as their functional capacities.Our results show a diverse pattern of TCR qualities and give insights into dynamics of neoantigen-specific T-cell responses in dependence of tumor heterogeneity.(3) We have developed novel immunoimaging strategies to track tumor-reactive T cells in vivo (Mall et al., Cancer Reserach 2016; Yusufi et al., Theranostics 2017). We have demonstrated high sensitivity and were also able to detect heterogeneity of tumor-reactive T cells within the tumor reflecting diverse stages of tumor rejection. Recently, we have additionally developed a novel immunoimgaing strategy to detect endogenously tumor-reactive T cells in vivo (Mayer&Mall et al. Theranostics 2018). Thereby, we have shown that in-depth functional investigation of immunoimaging approaches is essential for safe and successful clinical translation. Taken together, we have developed comprehensive state of the art immunomonitoring tools providing the base for understanding anti-cancer immune responses highly relevant for the development of equally safe and effective T-cell based immunotherapies to fight cancer.

References

  1. Audehm S, Glaser M, Pecoraro M, Bräunlein E, Mall S, Klar R, Effenberger M, Albers J, Bianchi HO, Peper J, Yusufi N, Busch DH, Stevanovic S, Mann M, Antes I, Krackhardt AM: Key features relevant to select antigens and TCR from the MHC mismatched repertoire to treat cancer; Front Immunol 2019; 10: 1485; doi: 10.3389/fimmu.2019.0148
  2. Albers J, Ammon T, Gosmann D, Audehm A, Thoene S, Winter C, Secci R, Wolf A, Stelzl A, Steiger K, Ruland J, Bassermann F, Kupatt C, Anton M, and Angela M Krackhardt: Gene editing enables T cell engineering to redirect antigen specificity for potent tumor rejection; Life Science Alliance 2019, doi: 10.26508/lsa.201900367.
  3. Mayer KE, Mall S, Yusufi N, Gosmann D, Steiger K, Russelli L, Bianchi H, Audehm S, Wagner R, Bräunlein E, Stelzl A, Bassermann F, Weichert W, Weber W, Schwaiger M, D`Alessandria C, Krackhardt AM: T-cell functionality testing is highly relevant to developing novel immuno-tracers monitoring T cells in the context of immunotherapies and revealed CD7 as an attractive target; Theranostics 2018; 8: 6070-6087.
  4. Yusufi N, Mall S, Bianchi HO, Steiger K, Reder S, Klar R, Audehm S, Mustafa M, Nekolla S, Peschel C, Schwaiger M, Krackhardt AM, D`Alessandria C: In-depth characterization of a TCR-specific Tracer for sensitive detection of tumor-dericted transgenic T cells by Immuno-PET; Theranostics 2017; 7(9):2402-2416
  5. Bassani-Sternberg M, Bräunlein E, Klar R, Engleitner T, Sinitcyn P, Audehm S, Straub M, Weber J, Slotta-Huspenina J, Specht K, Martignoni ME, Werner A, Hein R, H Busch D, Peschel C, Rad R, Cox J, Mann M, Krackhardt AM: Direct identification of clinically relevant neoepitopes presneted on native human melanoma tissue by mass spectrometry; Nat Commun 2016; 7:13404. doi: 10.1038/ncomms13404
  6. MallS, YusufiN, WagnerR, KlarR, BianchiH, Steiger K, StraubM, AudehmS, LaitinenI, AichlerM, PeschelC, ZieglerS, MustafaM, SchwaigerM, D`AlessandriaC, Krackhardt AM: Immuno-PET imaging of engineered human T cells in tumors; Cancer Research 2016; 76: 4113-23.
  7. Klar R, Schober S, Rami M, Mall S, Merl J, Hauck SM, Ueffing M, Admon A, Slotta-Huspenina J, Stevanovic S, Oostendorp RAJ, Busch DH, Peschel C, Krackhardt AM: Therapeutic targeting of naturally presented myeloperoxidase derived peptide ligands in myeloid leukemia cells by TCR-transgenic T cells; Leukemia 2014, 28: 2355-2366.

Acknowledgement

The work was supported by grants to A.M. Krackhardt from Deutsche Krebshilfe (110281), Wilhelm Sander-Stiftung (2015.030.1), Deutsche Forschungsgemeinschaft (DFG) (SFB824/C10) and the Technical University of Munich and International Graduate School of Science and Engineering (IGSSE).

Keywords: Cancer immunotherapy, Immunoimaging, PET-CT, T-cell tracking