Quando e come inserire l’immunoterapia nella strategia terapeutica

(1)

Unit of Investigative Clinical Oncology Istituto di Candiolo (IRCCS)

Immunoterapia nei tumori della mammella, utero

e ovaio; quando e come

(2)

Direzione Oncologia Clinica Investigativa, IRCC Candiolo

 Travel Grants from

 Astra Zeneca

 Roche

 Speaker’s Honoraria from

 Astra Zeneca

 Roche

 Novartis

Disclosures (last two years)

(3)

Commons in breast, ovarian and gynaecological cancers treated with checkpoint-inhibitors

Avelumab, TNBC Nivolumab, ovarian cancer

Dirix et al, Breast Cancer Res Treat 2017 Hamanishi et al, J Clin Oncol 2015

Pembrolizumab, endometrial cancer

Ott et al, J Clin Oncol 2017

Pembrolizumab, cervical cancer

Frenel et al, J Clin Oncol 2017

(4)

Tumor Neoantigens Immune infiltrate

CXCL9 CXCL10

IFN-ɣ

Tumor Metabolism

• PH

• LDH

• Lactate

Reduced sensitivity to immune effectors

Tumor

Inflammation

• VEGF-A

• IL1

• IL6

• IL17

• CSFs

• CSCL1

• E2

• CRP

• IDO

PD-L1

(5)

Multidimentional biomarker

Subject Immune status Lymphocytes

Netrophil/Lympocyte ratio MDSC

Tumor Neoantigens Tumor Metabolism

Reduced sensitivity to immune effectors

Tumor

Inflammation Immune infiltrate

Presence of

checkpoints

(6)

The cancer immunogram

Blank et al, Science 352;658, 2016

(7)

Mutational Load of Human Cancers

Alexandrov et al, Nature 500;415, 2013

(8)

 Some hystological subtypes display a high mutational burden in the primary, newly diagnosed cancer

 In these histological subtypes, a lympocitic infiltrate is frequent in early disease

 A lympocitic infiltrate is prognostic

Common aspects of Breast and

Gynaecological Cancers

(9)

Keynote-086; sTIL levels correlate

with tumor response

(10)

Keynote-086: PD-L1 and sTIL

levels are correlated

(11)

Keynote-086; sTILS levels tend to decrease

during the natural history of breast cancer

(12)

Reduced expression of MHC class I after several lines of chemotherapy

Andrè et al, ESMO 2014, abstr 3510

(13)

Keynote-086:% of TILs in

metastatic sites

(14)

sTILS tend to decrease during the natural history of the disease

Luen et al. Lancet Oncol 18;52, 2017

(15)

Immunogram; late stage disease

1 3

3 1

1

3 Subject Immune status

Tumor Neoantigens

Tumor Metabolism

Sensitivity to immune effectors

Tumor

Inflammation Immune infiltrate

Presence of

Checkpoints

(16)

Immunogram; metastatic disease, first-line

1 3

3 1

1

3 Subject Immune status

Tumor Neoantigens

Tumor Metabolism

Sensitivity to immune effectors

Tumor

Inflammation Immune infiltrate

Presence of

Checkpoints

(17)

Earlier stage disease

1 3

3 1

1

3 Subject Immune status

Tumor Neoantigens

Tumor Metabolism

Sensitivity to immune effectors

Tumor

Inflammation Immune infiltrate

Presence of

Checkpoints

(18)

 Novel Vaccines

 Oncolytic Virus

 Co-Stimulatory Molecules

 Targeted Therapy

 Radiation

 Chemotherapy

 Adoptive Cell Therapy

Combinatorial strategies

Non T Cell Inflamed

(19)

Neoadjuvant Pembrolizumab; the I- SPY 2 study

Nanda; ASCO 2017

(20)

Neoadjuvant immunotherapy may be better than adjuvant immunotherapy

Liu et al, Cancer Discov 6;1382, 2016

(21)

No differences between adjuvant or neoadjuvant chemotherapy

Liu et al, Cancer Discov 6;1382, 2016

(22)

Neoadjuvant vs Adjuvant trastuzumab- (retrospective)

Effect confined to patients with ER- tumors.

Palmieri et al, Oncotarget epub 2015

(23)

 When?

 First-line metastatic disease

 Early disease

• Neoadjuvant!

 How

 Alone

 With drugs that can modulate positively the parameters of the immunogram

Conclusion

(24)

Relationship between Tumor Mutational Burden and Microsatellite Instability

Ovary Endometrioid

Carcinoma

Uterus endometrial adenocarc.

NOS

Endometrioid

Chalmers et al; Genome Medicine 9;34, 2017