combinations in immunotherapy - umcg...combinations in immunotherapy tjn hiltermann longarts umcg...

Combinations in immunotherapy

TJN Hiltermann Longarts UMCG Groningen

Leek symposium 9-11-2016

Financial disclosures • Adviesraad BMS, AZD, Merck, Boehringer, Pfizer

Tijd (maanden)

Ove

rlevi

ng (%

)

Betere selectie patiënten en/of combinatie PD1 + RTx/biological?

PD1/ PD-L1

Biological o f Chemotherapie

HOE VERDER?

Hoe verder met immunotherapie

• PD-L1 als biomarker • Combinatie studies • Mogelijke rol histologie

2nd line treatment NSCLC: Nivolumab checkmate studies

17 (squamous)

57(non squamous)

Brahmer N Engl J Med 2015

Median Overall survival 1-Yr Overall survival

EMA approval independent of PD-L1

Borghaei N Engl J Med 2015

1st line treatment NSCLC: pembrolizumab

Reck N Engl J Med 2016

Selection: PD-L1≥50%

Keynote 24

500 (26%) PD-L1≥50% 305 (16%) in study 2nd line keynote-10: 442 (16%) PD-L1≥50%

PD-L1 as biomarker

• Obligatory in first line treatment (aprox 16% of patients)

• Not needed for second line treatment

• Enrichment of patients by higher cut off levels (RR 40-50%)

Moving forward?

• Studies combining PD-(L)1 inhibitor with chemotherapy

• Studies combining PD-(L)1 inhibitor with other checkpoints

• Studies combining PD-(L)1 inhibitor with radiotherapy

Combining 2nd line chemotherapy with PD-1

Langer Lancet Oncology 2016

Naiyer A. Rizvi et al. JCO 2016;34:2969-2979

Combining firstline chemotherapy and PD-1 inhibitor in NSCLC

N=11 N=15 N=15 N=13

No clear association could be discerned between PD-L1 expression and PFS or OS (Data Supplement), including assessments of higher expression levels of PD-L1

Fase III studies in NSCLC combining PD-(L)1 inhibitor with other checkpoint inhibitor

• Mystic trial (first line): durvalumab vs durvalumab + tremelimumab vs chemotherapy

• Neptune trial (first line) durvalumab+tremelimumab vs chemotherapy • Arctic trial (2nd line): Chemotherapy vs durvalumab vs durvalumab and

tremelimumab vs tremelimumab • CheckMate 227 (first line) Nivolumab, or nivolumab + ipilimumab, or

nivolumab + chemotherapy, vs chemotherapy • Checkmate 722 (2nd line EGFRm): Nivolumab + chemotherapy or nivolumab +

ipilimumab vs chemotherapy

Presenter

Presentation Notes

Checkmate 027 ook noemen

Radiotherapy and immunotherapy

• Meerdere studies lopen hiernaar • Volgt evt studie UMCG

Presenter

Presentation Notes

Change of balance of tumor-infiltrating cells after 30-Gy LTI. A, mice with 21-day tumors received a single dose of LTI (30 Gy). Tumor-infiltrating mononuclear cells were analyzed 14 days after LTI completion. Control tumor-bearing mice received no LTI and cells were analyzed at day 35. Representative stainings of CD4+ and CD8+ T cells, MDSCs (myeloid derived supressor cells CD11b positive), and TAMs are shown as well as the expression of PD-1 and Tim-3. B, immunohistochemistry of tumors at day 35 that were untreated or received 30-Gy LTI at day 21. Tumor tissue sections were stained with anti-CD3 and anti-CD11b antibodies using a two-stage procedure. CD11b+-red, CD3+ is green and DAPI staining is blue. C, kinetics of tumor-infiltrating cells after LTI was analyzed at days 1, 2, 3, 6, and 14 after LTI that are days 22, 23, 24, 27, and 35 after tumor induction, respectively. Cell subsets (CD11b Gr-1hi, CD11b Gr-1lo, CD11c, CD4+, and CD8+; n = 8) are shown as a mean percentage ± SE among live mononuclear cells in tumor. D, kinetics of tumor-infiltrating cells after LTI was analyzed at days 1, 2, 3, 6, and 14 after LTI that are days 22, 23, 24, 27, and 35 after tumor induction, respectively. Cell subsets (CD11b Gr-1hi, CD11b Gr-1lo, CD11c, CD4+, and CD8+) are shown as a mean absolute number ± SE per mg of tumor (n = 8).

KAN HET SLIMMER?

No response to immuno Rx as shown by rebiopsy

Biomarker status and response to PD-L1 inhibitor

RS Herbst et al. Nature 515, 563-567 (2014)

Potential characteristics of immunogenic and nonimmunogenic tumors

P. Sharma and J.P. Allison Science 2015;348:56-61

Om tot response te komen heb je combinatie Rx nodig bij niet immunogene tumor

Presenter

Presentation Notes

Potential characteristics of immunogenic and nonimmunogenic tumors. (A) Tumor tissue depiction indicating tumor cells and an invasive margin (dotted line), which may delineate separation of tumor cells from stromal components. Evaluation of tumor tissues may reveal an immunogenic tumor microenvironment consisting of many immunologic markers, including CD8 T cells, CD4 T cells, PD-L1, granzyme B, and CD45RO, which may be effectively treated with immune checkpoint therapy to elicit clinical benefit. (B) Tumor tissues that lack expression of many immunologic markers may indicate a nonimmunogenic tumor microenvironment, which may require combination therapies consisting of an agent to create an immunogenic tumor microenvironment plus an immune checkpoint agent to further enhance the immune response for clinical benefit.

Daniel S. Chen and Ira Mellman

The cancer immune cycle

The tumor immunity continuum

Priti S. Hegde et al. Clin Cancer Res 2016;22:1865-1874

Presenter

Presentation Notes

The tumor immunity continuum. Representative images of tumor CD8 IHC show three patterns of T cells associated with tumor cells. Tumors with preexisting immunity are represented by abundance of TILs, dense functional CD8+ T-cell infiltration reflected by increased IFNγ signaling, expression of checkpoint markers, including PD-L1, and high mutational burden. These characteristics reflect highly inflamed tumors. Despite high mutational burden, tumors with the excluded infiltrate or stromal T-cell phenotype are represented by increased influence of immunosuppressive reactive stroma, myeloid-derived suppressor cells (MDSC), and angiogenesis, all of which prevent infiltration of T cells into the tumors or suppress activation of T cells in the tumor milieu. Finally, immunologically ignorant tumors that contain very low infiltration of T cells are genomically stable with highly proliferating tumor cells. These are representative of noninflamed tumors.

Immune exhausted

Inflamed

Immune Desert (ignorant)

+ =

Agents that promote effective priming Eg OX40, αCTLA4, CD137

Agents that promote tumor cell death Eg Chemotherapy, CAR-T vaccines, Radiotherapy, STING Targeted therapy Talimogene Laherparepvec=T-VEC

Address the barriers to T-cell entry into the tumor Eg αVEGF, chemokine agonists/antagonis, TCBs

Increase responses in PD-L1+ tumors: Eg αLAG-3, αTIGIT, αIDO, OX40

AACR 2016 Hegde PS

The tumor immunity continuum and cancer immune cycle

Presenter

Presentation Notes

High IDO results in strong inhibition of T-cell mediated responses by blocking T-cell activation and inducing T-cell apoptosis TAM: tissue associated macrophages-> promote tumor escape by breaking down basemant membrane around proliferating tumor cells-> tumor escape CSF-1 overexpressed in many tumors results in TAM OX40 acts on antigen stimulated T cells, not on native T cells. Can reverse anergic state of T cells and therby enhance tumor immunity Talimogene Laherparepvec= live , attenuated herpes (HSV-1) engineered to produce GM-CSF. Intratumoral injection-> lysis of tumor cells, releasing tumor antigens. GM-CSF produced by virus promotes AG presentation and processing by DC (dendritic cells).

Conclusies

• Door patiënten en met name tumor goed te karakteriseren zullen we verder kunnen komen met de behandeling van gemetastaseerde kanker patiënten: − PD-L1 is niet het (hele) verhaal − Biopten voor behandeling steeds relevanter (inflamed vs

non-inflamed, Treg, TAM, MDSC etc) voor begrip van tumor responsen

− Combinaties van behandelingen (gestuurd door immunohistologie) zijn volgende stap in behandeling

PD-(L)1 inhibitors may become the backbone in treatment of (Lung)

cancer

Sent us your patients

Behandeling wordt steeds complexer

Motto: Makkelijker kunnen we het u niet maken

Multiple choice vragen

1. Belangrijkste parameter voor succes bij immunotherapie met checkpoint inhibitors is op dit moment:

a) PD-(L)1 status van tumor b) Histologie van tumor c) Aanwezigheid van tumor infiltrerende ontstekingscellen d) Type ontstekings infiltraat in tumor

2. Belangrijkste parameter voor verbetering succes bij immunotherapie met checkpoint inhibitors wordt

a) PD-(L)1 status van tumor b) Histologie van tumor c) Aanwezigheid van tumor infiltrerende ontstekingscellen d) Type ontstekings infiltraat in tumor

Herbst et al Lancet 2016; Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, NSCLC (KEYNOTE-010)

1224 (45%) no PD-1

=30% 1665 (62%)

Selection of patients

442 (16%) PD-L1≥50%

Presenter

Presentation Notes

CONSORT DIAGRAM KEYNOTE 10 2ND LINE

combinations in immunotherapy - umcg...combinations in immunotherapy tjn hiltermann longarts umcg...

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