ESCMID Online Lecture Library @ by Author

The diverse monoclonal antibodies in immunology and medical oncology: relevance for infectious diseases

Dra. Isabel Ruiz Camps ESCMIDHospital Online Universitari Lecture Vall d’Hebron Library @ by authorBarcelona Disclosure

• Astellas • Gilead Sciences • MSD • Novartis • Pfizer

ESCMID Online Lecture Library @ by author A huge topic for such a ESCMIDshort Online time Lecture Library @ by author natalizumab antiTNF antiCD20: rituximab, obinutuzumab, ofatumumab gemtuzumab (antiCD33) alemtuzumab (antiCD52)

daratumumab (antiCD38) Inotuzumab (antiCD22) Brentuximab (CD30) Seculinumab (anti IL-17) Tocilizumab (antiIL6) PI3K inhibitors PARP inh: olaparib, Guselkumab (anti IL12/23) rucaparib (copanlisib, more ... Roxulitinib, tofacitinib (JAK inh) Urelumab (CD137 R)

Immunotherapy: ipilimumab TK inhibitors : Imatinib, dasatinib, Belimumab (antiBAFF) (CTLA-4), tremelimumab (CTLA-4), masitinib, bosutinib, nilotinib, fostamatinib nivolimumab (PD1/PDL1), (spleen), ibrutinib (BTK), alisertib (ATK), Pembrolizumab (PD1), more...... afatinib Cabozantinib: MET, RET, VEGFR2 HER2/neu:ESCMID trastuzumab, lapatinib Online VEGFR: bevacizumabLecture, LibrarymTOR: temsirolimus sorafenib, sunitinib EGFR: cetuximab, panitumumab, MAPK inh: dabrafenib, vemurafenib erlotinib, gefitinib Selinexor (XPO1 antagonist) @ by author Trametinib (MEK inh) Index

• Background • Biological therapies for immunological diseases and risk of infection • Biological therapies for cancer – Target pathways – Risk of infection • Prevention ESCMID Online Lecture Library @ by author What are we talking about?

• development of drugs directed at specific molecular targets for the treatment of disease. • “biologic therapies or biologicals ” : monoclonal antibodies, receptor analogues, and chimeric small molecules designed to bind to or mimic their molecular targets • Advantages: potency, specificity, theoretically ESCMIDdecreased side Online effects Lecture Library @ by author Problems in determining causality between biological therapy and infection:

• Underlying disease causes immunosupression • Small number events difficult establish a true association • Large number of confounders

ESCMID Online Lecture Library @ by author Index

Drug name Serious infections Strategy anti-TNF: Bacterial infections (serious and listeria, TST/IGRA inflimimab, salmonella…) , TB, MOTT, fungal infections HBV detection and adalimumab, (endemic and opportunistic), CMV, HB prevention etanercept reactivation, papillomavirus, VZV, vaccination toxoplasmosis, leishmaniasis Overwhelming bacteremia, CMV, HSV, VZV, Alemtuzumab HB reactivation, adenovirus, B19 parvovirus TST/IGRA TB, MOTT, PJP, fungal infections (endemic PCR CMV or prophylaxis (anti-CD52) and opportunistic) and others TMP-SMX

Rituximab PML, HB and HC reactivation, bacterial, VZV, Vaccination, cotrimoxazole? (anti-CD20) HSV, B19 parvovirus, monitoring

Pneumonia, cellulitis, TB, unspecified Anakinra mycobacterial and fungal infections PML, HHV, influenza, PJP, MAI, Aspergillus, JC detection Natalizumab other TocilizumabESCMID Onlineneutropenia Lecture Librarydecrease the doses @ by author Index

ESCMID Online Lecture Library @ by author High grade infection: RR 1.49(95% CI, 1.33-1.66: p<0.001) Independent time Colorectal cancer, NSCLC and SCCHN

Febrile neutropenia: RR 1.27(95% CI, 1.09-1.48: p=0.002) Longer duration >3.1 months NSCLC 14,957 patients ESCMID Online Lecture Library @ by author a severe infection is 1.34-fold higher in patients treated with anti-EGFR MoAbs, while the use of anti-EGFR MoAbs does not significantly increase the risk of fatal infections.

severe infections might possibly occur early in the treatment with anti-EGFR MoAbs.

colorectal cancer, non-small-cell lung cancer, and head and neck cancer. 14,066 patients

cisplatin or irinotecan may increase the risk of severe infections ESCMID Online Lecture Library

@ by author • 62 years, male • Colorectal cancer different lines of treatment ICECREAM (cetuximab), 6 doses. • Pain in PAC area (fever, pain, erythema, edema 48h)

ESCMID Online LectureNegative BloodLibrary culture PAC culture S.aureus @ by author 2014

ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMIDBlood culture Online + S.aureus Lecture Library @ by author 1.45 fold higher risk of infection

1.59 fold increase in the risk of high- grade infection

Fatal infections 0.9%

Cumulative exposure (not stst. sign)

Increased risk: colorectal cancer, NSCLC, breast cancer and gastric cancer, used with taxanes, capecitabine, gemcitabine and oxaliplatin

Patients with active or recently active infections excluded from clinical trials, ESCMID Online Lectureincidence of infections Library could be widely underreported @ by author ESCMID Online Lecture Library @ by author 10,0094 patients from 13 trials were included

Increased risk of high-grade infection: RR 1.21(95% CI, 1.07-1.37: p=0.002) Increased risk of febrile neutropenia: RR 1.28(95% CI, 1.08-1.52: p=0.004)

Incidence of high-grade infection due to trastuzumab 8.5% (95% CI, 4.5-15.4%) Incidence of febrile neutropenia 12% (95% CI 8.1-17.4%)

Risk factors associated with infections could not be established

Higher incidence in the combination therapy ESCMID Online Lecture Library @ by author Biological Therapies and their risk of infection

To summarize:

Drug name Serious infections Strategy Cetuximab Bacterial (S.aureus, MRSA), fungal Close monitoring Sepsis, febrile neutropenia

Close monitoring Panitumumab Similar to cetuximab

Bacterial and fungal infections Close monitoring Bevacizumab Neutropenic fever, sepsis, pneumonitis More frequent in combination Mild bacterial infections (UTI, respiratory) Close monitoring Trastuzumab Febrile neutropenia more frequent in -- ESCMIDcombination Online therapy Lecture Library @ by author Different Pathways Multi-kinase inhibitors

The inhibition phosphatidylinositol 3-kinase (PI3K)-AKT- mTOR reduces generation and supresses secretion of proinflammatoryESCMID cytokines. Online Lecture Library Attenuated immunoresponse @ by author Clin Cancer Res. 2015 Feb 3.

PI3K-AKT- mTor mechanisms of infection not fully understood Regulates production of cytokines in innate immuneESCMID cells Online Lecture Library @ by author Risk of all grade and high-grade infection with single agent PI3K-AKT-mTOR inhibitors is 3.8 and 5.3 times higher, respectively, compared to other non-myelosuppressive targeted therapies

ESCMID Online Lecture Library @ by author To sum up

Higher risk of all grade (3.8%)/high-grade infections (5.3%), and higher if combined with chemotherapy or in dual combinations (sinergistic effect????)

138/140 (98.5%) had bacterial infections (urinary, respiratory), 2 HZV .

72% had one episode of infection and 28% > 2 episodes

9(6.4%) neutropenic and 43 (30%) lymphopenic (1.2 x 109/l ; range: 0.2-3.1 x 109/l).

The number of cycles of treatment was confirmed as a predictor of the risk of infection in the multivariate logistic mixed model (OR: 1.109, 95% CI: 1.02-1.19, p=0.008).

ResultsESCMID from this study Online will need Lectureto be validated Libraryin future phase II and phase III studies @ by author T-cell checkpoint blockade Mechanism of action of Ipilimumab and Nivolumab

ESCMID Online Lecture Library

Immune-related adverse events: rash, diarrhea, hepatitis Other: tremelimumab@ by (CTLA author-4), pembrolizumab (PD1) ESCMID Online Lecture Library Fournier’s@ gangreneby author, CMV viremia 76 y male SCLC S IV CBDP-VP 16 +/- ipilimumab (4 doses)

Bloody diarrhea Hypotension, tachycardia, hypoK+

steroids Copro negative CD toxine negative No lymphopenia

Bloody diarrhea persisted (>1 month) Colonoscopy: ulcers in all colon PCR/immunochemistry positive CMV CMV PCR 6500 copies ESCMIDGanciclovir/valganciclovir Online Lecture Library @ by author Can we prevent infection in these patients?

How to prevent these infections?

ESCMID Online Lecture Library @ by author General preventive measures

• Vaccination • Screening for latent infections – TB (active and latent-LTBI) – HBV/HCV – Imported diseases – Viral infections: HSV, VZV, CMV, HIV • Papilomavirus infection •ESCMIDP.jiroveci infection Online (follow Lecture up) Library @ by author

ESCMID Online Lecture Library @ by author Screening for TB

ESCMID Online Lecture Library @ by author Screening for HBV: algorithm

Rituximab or /and long IS Tenofovir /Entecavir DNA HBV. Start HBsAg+/HBcAb+ prophylaxis Short IS or no Rituximab Lamivudine DNA HBV+

HBsAg Rituximab or ChT . HBsAg-/HBcAb+ HBcAb Prophylaxis vs. monitor DNA VHB- Other IS: Monitor every 3 months ALT/DNA HBV HBsAg-/HBcAb- Vaccination ESCMID Online Lecture Library

@. by authorProvided by Dr. Mar Riveiro. Vall d’Hebron hospital IMPORTED DISEASE SCREENING PRIOR TO CHEMOTHERAPY FOR ONCO- HAEMATOLOGICAL MALIGNANCIES AND BONE MARROW TRANSPLANT. Hospital Vall d’Hebron. Barcelona

Latin Caribean North Sub- Asia America islands Africa and saharan Middle Africa East Blood test, yes yes yes yes yes TRx, TST/IGRA, HIV, HBV, HCV, syphilis, toxoplasma Feces (2) yes yes yes yes yes

Strongyloides yes yes yes yes yes stercolaris serology Plasmodium Amazonian yes no yes yes PCR area

Trypanosoma yes no no no no cruzi serology

ESCMIDSchistosoma Brasil Onlineyes noLecture yes Libraryno mansoni serology@ by author IMPORTED DISEASE SCREENING PRIOR TO CHEMOTHERAPY FOR ONCO- HAEMATOLOGICAL MALIGNANCIES AND BONE MARROW TRANSPLANT.

Hospital Vall d’Hebron. Barcelona 42 patients 21 (50%) at least one infection

ESCMID Online Lecture Library @ by author Cotrimoxazole: - PJP - Listeria - Legionella - Salmonella - Toxoplasma - Isosopora - Nocardia - other: enterobacteries, Haemophilus, Moraxella, Stenotrophomonas, Staphylococcus...

ESCMID Online Lecture Library @ by author *

Biodabaser*: risk for infection 53/1000 person- years- Infliximab and adalimumab higher risk Risk PJP (Japan) 0.18%-0.4% ESCMIDPJP: >65y, COPD, use MTX or steroids Online Lecture Library BSRBB: 1TMP-SMX susceptible infection occurs for every 1233 patients year of follow-up Most infections@ occurby within firstauthor year ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author Cotrimoxazole in Vall d’Hebron Hospital

• use of steroids plus biologicals • a manteined total lymphocyte count <1000 cell/ mm3 • if > 2 immunosupressors • rituximab in HIV+ and in the other patients if persistent lymphopenia • alemtuzumabESCMID (no in renalOnline Tx) Lecture Library

@ by author Sometimes …

• 65 y breast cancer • docetaxel +bevacizumab • 3w TC: PR • 1w fever+dispnea+dry cough

• pO2 66, 600 lymphocytes

ESCMID Online Lecture Library @ by author Messages to take home

Exponential increase in number of biological therapies in immunological and cancer patients.

The high risk for infection that cancer patients present could be increased by some targeted therapies (large number of confounders)

Notify infections, prospective trials could be interesting in order to know real incidence. ESCMID Online Lecture Library @ by author Messages to take home

Be aware. Adverse events mimic infections and infections affect neutropenic and non neutropenic patients

Incidence of opportunistic infection is unknown

Prevention and early diagnosis could be the clue ESCMID Online Lecture Library @ by author