Research area 3: Profiling of T-cell receptors as a tool to identify T-cell reactivities

The T-cell repertoire serves as a “fingerprint” of the immune response, and can reveal information about the nature of the antigens eliciting a T-cell response. In collaboration with clinical collaborators we have used the profiles of T-cell repertoires of patients with multiple sclerosis and with autoimmune liver disease to elucidate characteristics of targets of T cells in these diseases.

 

Selected references:

High-throughput T-cell receptor sequencing across chronic liver diseases reveals distinct disease-associated repertoires.
Liaskou E, Klemsdal Henriksen EK, Holm K, Kaveh F, Hamm D, Fear J, Viken MK, Hov JR, Melum E, Robins H, Olweus J, Karlsen TH, Hirschfield GM.
Hepatology. 2016 May;63(5):1608-19. doi: 10.1002/hep.28116. Epub 2015 Sep 30.

Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease.
Henriksen EK, Jørgensen KK, Kaveh F, Holm K, Hamm D, Olweus J, Melum E, Chung BK, Eide TJ, Lundin KE, Boberg KM, Karlsen TH, Hirschfield GM, Liaskou E.
J Hepatol. 2017 Jan;66(1):116-122. doi: 10.1016/j.jhep.2016.09.002. Epub 2016 Sep 17.

High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells.
Lossius A, Johansen JN, Vartdal F, Robins H, Jūratė Šaltytė B, Holmøy T, Olweus J.
Eur J Immunol. 2014 Nov;44(11):3439-52. doi: 10.1002/eji.201444662. Epub 2014 Sep 16.

Research area 2: Targeting of self-antigens

Therapeutic antibodies recognize "normal" cell surface proteins with cell type-restricted expression. A good example is antibodies to the B-cell antigen CD20, which are used for treatment of leukemia and lymphoma. These antibodies kill normal and malignant B cells indiscriminately. Yet, the ability to limit cytotoxicity to a single cell type represents an important step forward compared to chemotherapy and radiation therapy. The major advantage of self-antigens as therapeutic targets (relative to cancer mutations) is that the same target can be used in all patients with a particular cancer type. Similarly, CARs (chimeric antigen receptors) target normal cell surface proteins like CD19 to which the antibody portion of the receptor binds. Adoptive cell therapy using T-cells genetically equipped with CARs has been a tremendous success in the treatment of B-lymphoid leukemia and lymphoma. In spite of worldwide efforts it has, however, proven difficult to find similarly good targets in other leukemias, and in other cancer types. The number of candidate self-antigens that could be targeted in cancer can be increased dramatically with the use of T-cell receptors as alternatives to CARs in adoptive cell therapy. The reason is that T cells, in contrast to CARs/antibodies, have the ability to recognize peptides from intracellular proteins, and the large majority of cellular proteins are inside the cell. A major focus in our group is to direct T-cell receptors to peptides derived from self-antigens expressed on cancer cells by use of foreign (allogeneic) HLA for antigen presentation.

Project

Using T cell receptors from “non-tolerized” donors to target self-antigens

To overcome immunological self-tolerance for "normal" proteins, our laboratory has taken a new approach that involves peptide presentation on foreign HLA molecules. We have shown that it is feasible to obtain T cells from one individual that selectively kill defined cell types from another individual with a different tissue type. The recognition elements are peptides from "normal" proteins with cell type-restricted expression, bound to a tissue type molecule of the target individual. A multitude of novel targets and their cognate T-cell receptors have been isolated from healthy donors using our patent-pending technology. T cells engineered to express receptors recognizing these targets are expected to be useful to treat subtypes of leukemia or lymphoma in all patients who share the same tissue type molecule (HLA-A2; shared by 50% of Caucasians).

Selected references

Kumari SWälchli SFallang LEYang WLund-Johansen FSchumacher TNOlweus J (2013)
Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes
Proc Natl Acad Sci U S A111 (1)403-8
PubMed 24344295

Abrahamsen IWKjellevoll SGreve-Isdahl MMensali NWälchli SKumari SLoland BFEgeland TKolstad AOlweus J (2011)
T cells raised against allogeneic HLA-A2/CD20 kill primary follicular lymphoma and acute lymphoblastic leukemia cells
Int J Cancer130 (8)1821-32
PubMed 21630262

Abrahamsen IWStronen EWälchli SJohansen JNKjellevoll SKumari SKomada MGaudernack GTjonnfjord GToebes MSchumacher TNLund-Johansen FOlweus J (2010)
Targeting B cell leukemia with highly specific allogeneic T cells with a public recognition motif
Leukemia24 (11)1901-9
PubMed 20844564

Stronen EAbrahamsen IWGaudernack GWälchli SMunthe EBuus SJohansen FELund-Johansen FOlweus J (2009)
Dendritic cells engineered to express defined allo-HLA peptide complexes induce antigen-specific cytotoxic T cells efficiently killing tumour cells
Scand J Immunol69 (4)319-28
PubMed 19284496

Mensali NYing FSheng VOYang WWalseng EKumari SFallang LEKolstad AUckert WMalmberg KJWälchli SOlweus J (2016)
Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA
Oncoimmunology5 (5)e1138199
PubMed 27467957

Research area 1: Targeting of cancer-specific mutations

Immunotherapy with checkpoint inhibitors, such as anti-PD1 and anti-CTLA4, activates T cells capable of recognizing peptides from mutated proteins (neo-antigens), representing a major breakthrough in cancer treatment. However, while all cancers harbor mutations, patient T cells rarely elicit a curative response, and the majority of patients eventually relapse following checkpoint inhibition. It is now clear that patient T cells only recognize a minor subset of mutations in a tumor. A major focus of the lab is to develop novel technologies that can improve on the identification and targeting of cancer-specific mutations that can evoke an immune response (immunogenic neoantigens). Our goal is that such technologies can be used to improve on the therapeutic outcome of patients treated with immunotherapy.

Projects

Targeting mutations that are neglected by the immune system of the patient with healthy donor T cells

In collaboration with Ton Schumacher, partner on our K.G. Jebsen center for Cancer Immunotherapy, we have recently demonstrated that healthy donor T cells recognize many more mutations than are “seen” by the patient tumor-infiltrating lymphocytes. We are now studying the rules that determine why some mutations can elicit T cell responses why others cannot, using healthy donor T cells.

Selected references:

Strønen EToebes MKelderman Svan Buuren MMYang Wvan Rooij NDonia MBöschen MLLund-Johansen FOlweus JSchumacher TN (2016)
Targeting of cancer neoantigens with donor-derived T cell receptor repertoires
Science352 (6291)1337-41
PubMed 27198675

Commentaries:
In Science: IMMUNOTHERAPY. Outsourcing the immune response to cancer. [Science. 2016]
In NEJM: The Antigenicity of the Tumor Cell — Context Matters [NEJM, 2017]

Characterizing tumor-reactive T cells and their targets in cancer patients

We recently completed a successful trial (LYMVAC-1 protocol, PI: Arne Kolstad) testing an in-house developed regime for local immunotherapy in patients with follicular lymphoma. Thirty-six percent of the patients in LYMVAC-1 achieved clinical responses. In collaboration with our clinical partner, senior oncologist Arne Kolstad (Dept of Oncology, Radiumhospitalet), we are currently investigating into the targets of the tumor-reactive T cells of biobanked material from the study, and a follow-up clinical trial has recently been started (LYMVAC-2).

Patient 2 in the Lymvac-1 study: complete remission after 6.5 years

Selected references:

Kolstad AKumari SWalczak MMadsbu UHagtvedt TBogsrud TVKvalheim GHolte HAurlien EDelabie JTierens AOlweus J (2014)
Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma
Blood125 (1)82-9
PubMed 25293773

Kolstad AOlweus J (2015)
"In situ" vaccination for systemic effects in follicular lymphoma
Oncoimmunology4 (7)e1014773
PubMed 26140239

 

Discovery of auto-antibody targets and exploring their utility as biomarkers of T cell reactivity in cancer patients

In collaboration with the group of Fridtjof Lund-Johansen, partner on K.G. Jebsen Center for Cancer Immunotherapy, we have developed protein array technology useful to identify the targets of autoantibodies. The arrays are based on the MAP technology developed by Lund-Johansen and described in references (Wu W, Slastad H, de la Rosa Carrillo D, Frey T, Tjonnfjord G, Boretti E, Aasheim HC, Horejsi V, Lund-Johansen F. Antibody array analysis with label-based detection and resolution of protein size. Mol Cell Proteomics. 2009;8(2):245-257; Slaastad H, Wu W, Goullart L, Kanderova V, Tjonnfjord G, Stuchly J, Kalina T, Holm A, Lund-Johansen F. Multiplexed immuno-precipitation with 1725 commercially available antibodies to cellular proteins. Proteomics. 2011;11(23):4578-4582.)

Arrays with more than 10,000 full-length human proteins have been developed and are currently used to measure the reactivity of serum antibodies from large cohorts of patient sera before and after treatment with immunotherapy and other therapies. We have discovered a number of novel targets that are currently investigated further, also with regard to T-cell reactivity to peptides from the same targets. We believe that basic studies of the collaboration between T- and B-cells can bring important new insights into cancer immunity of therapeutic importance.


 

Research interests

Our group aims to develop new T-cell based concepts for cancer immunotherapy that overcome the major challenge of self-tolerance in cancer. To this end, one of our main strategies involves studies of how the immune system from healthy donors can target patient cancer cells. We have a strong focus on the development of new technologies that allow high-throughput identification of therapeutic targets that can evoke immune responses, as lack of immunogenic targets represents a major limitation in therapeutic efficacy. The group furthermore has a strong translational focus and performs penetrating mechanistic analyses in clinical trials together with our clinical partners.​ The group is a member of K.G. Jebsen Center for Cancer Immunotherapy (Center Director: Olweus).​