Radioimmunotherapy: Recent Advances and Current Opportuni�Es

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Internaonal Course on THERANOSTICS AND MOLECULAR RADIOTHERAPY

Radioimmunotherapy: recent advances and current opportunies

Thursday October 5, 2017

BOURGEOIS Mickaël, PharmD, PhD Radiopharmacist

Conﬂict of interest

No relevant affiliaons or financial involvement with any organizaon, company or enty with financial interest in RIT.

Scienﬁc interest: Nantes University Hospital: Clinical trial in RIT

ARRONAX Cyclotron: Producon of innovave isotopes (64Cu, 211At) And Radiopharmacy unit of Nantes University Hospital

French Naonal Instute of Health and Medical Research Nantes Cancer Research Center Team #13 : Nuclear Oncology Searching ﬁeld: - RIT (α, β-), Radiopepde therapy, phenotypic imaging,… - Interdsciplinary aspect: radiobiology,immunology, radiochemistry, radiopharmacy, radiophysic,… - Transfer from laboratory to paent (clinical trial in hospital Nuclear Medicine departement) Historical context of Radio-ImmunoTherapy (RIT)

- Classical nonspeciﬁc cytotoxic chemotherapies

- Targeted therapies

SCLC tumor cell (SEM) Immunotherapy

Köhler & Milstein Monoclonal Anbodies Nature 1975 Nobel prize 1984 Historical context of Radio-ImmunoTherapy (RIT)

Radio-Immunotherapy (RIT)

1978 – CarcinoEmbryonicAngen as a target for Immunotherapy detecon (Diagnosc applicaon) with 131I-mAb. Goldenberg D. New England Journal of Medicine 1987 – Therapy of B-cell Lymphoma (Therapeuc applicaon) with 131I-mAb. DeNardo S.J. Int. J. Biol. Markers

… Sll in progress

Radiotherapy pioneers: C. Regaud & A. Lacassagne (1926) Radioacvity “The ideal agent to treat cancer will be constuted by heavy elements, able to emit some radiaon … to destroy cancer cells” RIT principe

Speciﬁc angen

N H N H

- O O C C O O - N N

N N mAb = speciﬁc vector for cancer cell - O O C C O O - i.e. speciﬁc irradiaon of tumor cell

Cancer cell Speciﬁc irradiaon = goal of RIT (beer eﬀect with long accumulaon me)

NH COO-

N COO- - OOC N

N O

- OOC NH COO-

N COO- - OOC N

O N

- NH COO- OOC

N COO- - O OOC N NH N NH COO-

-OOC N

N COO- - OOC N

N O

O - OOC NH COO- NH

NH COO- N

O N COO- - NH N OOC N

NH COO- N COO- N - OOC N

N N -OOC O N COO- NH - - OOC N OOC NH COO- N

N -OOC

N COO- - OOC N

-OOC O

NH COO-

N COO- - OOC N

N -OOC Non speciﬁc irradiaon = adverse event (less with shorter circulaon me and high clearance from healthy O

NH COO-

N COO- - OOC N ssue) N

-OOC RIT principe

Speciﬁc angen

N H N H

- O O C C O O - N N

N N mAb = speciﬁc vector for cancer cell - O O C C O O - i.e. speciﬁc irradiaon of tumor cell

Cancer cell Speciﬁc irradiaon = goal of RIT (beer eﬀect with long accumulaon me)

Key of success:

NH COO-

N COO- - OOC N Good contrast between N O

- OOC NH COO-

N COO- - OOC N healthy and cancer ssue O N

- NH COO- OOC

N COO- - O OOC N NH N NH COO- Risk -OOC N

N COO- - OOC N

N O

O - OOC NH COO- Beneﬁt NH

NH COO- N

O N COO- - NH N OOC N

NH COO- N COO- N - OOC N

N N -OOC O N COO- NH - - OOC N OOC NH COO- N

N -OOC

N COO- - OOC N

-OOC O

NH COO-

N COO- - OOC N

N -OOC Non speciﬁc irradiaon = adverse event (less with shorter circulaon me and high clearance from healthy O

NH COO-

N COO- - OOC N ssue) N

-OOC RIT principe

Speciﬁc angen

N H N H

- O O C C O O - N N

N N mAb = speciﬁc vector for cancer cell - O O C C O O - i.e. speciﬁc irradiaon of tumor cell

Cancer cell

NH COO-

N COO- - OOC N

-OOC

NH COO-

N COO- - OOC N

N Irradiaon of tumor cell = OK -OOC

NH COO-

N COO- - OOC N

N O

- OOC NH COO-

N COO- - OOC N

O N

- NH COO- OOC

N COO- - O OOC N NH N NH COO-

-OOC N

N COO- - OOC N

N O

O - OOC NH COO- NH

NH COO- N

O N COO- - NH N OOC N

NH COO- N COO- N - O OOC N

N NH N -OOC O N COO- NH - NH -OOC -OOC COO N Irradiaon of distant cell NH COO- N

N N -OOC N COO- - OOC N N COO- - N OOC N (no ﬁxaon of mAb) = -OOC N O NH

NH COO-

-OOC N

N COO- Cross ﬁre eﬀect = OK - OOC N

-OOC

Irradiaon of healthy cell = BAD

NH NH COO- For many years:

N COO- - OOC N

N -OOC Haematological disease… Current limitaons of RIT

Abnormal 3D tumor neovasculature Stenosis (è), Arteriovenous shunt, blood ﬂow inversion, dead end ( ),…

Neoangiogenesis > Neolymphogenesis High Intersal pressure

Limitaon for passive diﬀusion (Fick’s principles)

100 μm

Konerding M.A. et al. Br.J.Cancer 2001 Current limitaons of RIT …or not

Abnormal 3D tumor neovasculature Stenosis (è), Arteriovenous shunt, blood ﬂow inversion, dead end ( ),…

Neoangiogenesis > Neolymphogenesis High Intersal pressure

Common Limitaon for passive diﬀusion (Fick’s principles) Misconcepon

100 μm In pracce, this poor limitaon seems to be overesmated Konerding M.A. et al. Br.J.Cancer 2001 Autoradiographic study with 125I-mAb 1 h post I.V. 6 h post I.V. 7 d post I.V.

Chen F.M. et al. J.Nucl.Med. 1990 The diffusion is more slowly but sufficient for a good tumor irradiaon by RIT Opmisaon way (if necessary): co-infusion with interleukin-2, chemical modificaon of mAb, posive pressure injecon (see « injecon way » slide),… Current limitaons of RIT …or not ( items that need to pay parcular aenon)

irradiaon parameters of RIT

NH COO-

vs N

N COO- - OOC N

-OOC

External beam radiotherapy Radioimmunotherapy High dose rate / Short me (relavely) Low dose rate / Long me (kinec of the mAb) Well known radiobiology eﬀect Unperfect known radiobiology eﬀect… - Dose response relaonship ? - Cell survival ?

Supply chain of radionuclides (Stumbling points)

NH COO-

N COO- - OOC N

Isotope choice: - Chemical process: Specific acvity, OOC emier type, half- Producon: cost & radionuclide purity, radiolabelling Radiopharmaceucal life, energy,.. availability yield, radiochemical purity,… quality Recent advances in RIT: mAb derivaves 1st mAb : Murine origin (high immunogenicity) Ag recognion (hypervariable regions – CDR) - Monospecific - Divalent - High affinity (Kd ≈ 10-9 M)

33 % murine 5-6 % murine 100 % murine 100 % Human 67 % Human 94-95 % Human Relavely former evoluon Pharmacokinec half-life (for RIT middle 2000’s): Immunogenicity Human An-Mouse Human An-Chimeric Human An-Humanized Anbody Anbody Anbody An-idiotypic (HAMA) (HACA) (HAHA) reacon ? Modiﬁcaon of mAb (Biochemist and immunochemist current work)

F(ab’)2 Fab’ Fab scFv di-scFv Reducon of half-life and kidney eliminaon Bispecific F(ab’) Bispecific mAb 2 chemically linked Recent advances in RIT: mAb derivaves 1st mAb : Murine origin (high immunogenicity) Ag recognion (hypervariable regions – CDR) - Monospecific - Divalent - High affinity (Kd ≈ 10-9 M)

F(ab’)2 Fab’ Fab scFv di-scFv Reducon of half-life and kidney eliminaon Bispecific F(ab’) Mainly for diagnosc purpose Bispecific mAb 2 chemically linked Used for RIT purpose: Clinical trial in Ovarian Carcinoma High efficacity, Renal side effects tolerable Pretargeng approach (Bäck et al. Cancer Biother Pharm 2009; Andersson et al. J. Nucl. Med. 2009) Recent advances in RIT: Pretargeng

Aﬃnity Enhancement System (AES)

1st step: IV injecon of bispeciﬁc anbody

- Bispecific mAb (affinity for tumor angen + specific hapten) - Non radioacve - Slow clearance

Hepac metabolism Tumor cell

Renal Eliminaon

… wait for the full eliminaon of bispeciﬁc mAb Recent advances in RIT: Pretargeng

Aﬃnity Enhancement System (AES)

2nd step: IV injecon of Radioacve hapten

radioacve Fast clearance Aﬃnity for the 2nd valence of the bispeciﬁc mAb

Rapid Renal Eliminaon Tumor cell = low toxicity Clinical validaons: Medullary thyroid carcinoma: mAb an-CEA x anDTPA-TL-In Delay between mAb (75mg/m2) and hapten (1.8 GBq/m2) injecon = 5 days Results: long term disease stabilisaon (RECIST Criteria) and minor toxicity (transient grade I-II hepac toxicity + grade III-IV leukopenia & thrombopenia) Kraeber-Bodere F. et al. J.Nucl.Med. 2006 Salaun P.Y. et al. J.Nucl.Med. 2012 Salun P.Y. et al. Eur.J.Nucl.Med.Mol.Imaging 2014

Recent advances in RIT: Radiosensizaon

Goal: potenate the therapeuc acon of RIT Paclitaxel + RIT (3.7 MBq)

Topoisomerase I inhibitor (Topotecan) Breast cancer Ng B. et al. Cancer Res. 2001

Pyrimidine analogs (Gemcitabine) RIT

alone Pancreac cancer Paclitaxel

Cardillo T.M. et al. Int.J.Cancer 2002 (2.22 Control

alone Anthracyclin compound (Doxorubicin) MBq

) Mulple myeloma Supiot S. et al. Clin.Cancer Res. 2005

Taxol derivaves (Paclitaxel®) Epidermoid carcinoma Adapted from Jang B.S. et al. Nucl.Med.Biol. 2012

Jang B.S. et al. Nucl.Med.Biol. 2012 Recent advances in RIT: Radiosensizaon

Goal: potenate the therapeuc acon of RIT Paclitaxel + RIT (3.7 MBq)

Topoisomerase I inhibitor (Topotecan) Breast cancer Ng B. et al. Cancer Res. 2001

Pyrimidine analogs (Gemcitabine) RIT

alone Pancreac cancer Paclitaxel

Cardillo T.M. et al. Int.J.Cancer 2002 (2.22 Control

alone Anthracyclin compound (Doxorubicin) MBq

) Mulple myeloma Supiot S. et al. Clin.Cancer Res. 2005

Taxol derivaves (Paclitaxel®) Epidermoid carcinoma Adapted from Jang B.S. et al. Nucl.Med.Biol. 2012

Jang B.S. et al. Nucl.Med.Biol. 2012 Preclinical proof: Co-administraon of « cold » drug & RIT = Synergic eﬀect Recent advances in RIT: Radiosensizaon

Goal: potenate the therapeuc acon of RIT Paclitaxel + RIT (3.7 MBq)

Topoisomerase I inhibitor (Topotecan) Breast cancer Ng B. et al. Cancer Res. 2001

Pyrimidine analogs (Gemcitabine) RIT

alone Pancreac cancer Paclitaxel

Cardillo T.M. et al. Int.J.Cancer 2002 (2.22 Control

alone Anthracyclin compound (Doxorubicin) MBq

) Mulple myeloma Supiot S. et al. Clin.Cancer Res. 2005

Taxol derivaves (Paclitaxel®) Epidermoid carcinoma Adapted from Jang B.S. et al. Nucl.Med.Biol. 2012

Jang B.S. et al. Nucl.Med.Biol. 2012 Preclinical proof: Co-administraon of « cold » drug & RIT = Synergic eﬀect

Grade 3-4 Proteasome inhibitor (Bortezomib®) Non-Hodgkin Lymphoma Elstrom R.L. et al. Leuk. Lymphoma 2015

Clinical proof: Phase I (toxicological study) To be connued… Recent advances in RIT: Innovave radionuclides Radioisotope choice (non exhausve…):

Decay Energy (keV) Range (mm) Isotope Half-life Other emission mode Avg. Max. Avg. Max. 125I 59.4 d Auger e- 3.2 - 22.7 ≈ 10 nm X, γ 131I 8.02 d β- 191.6 606.3 0.4 2.4 γ 90Y 64.0 h β- 933.7 2280.1 4.2 12 / 177Lu 6.65 d β- 149.3 498.3 0.3 1.5 γ 67Cu 61.83 h β- 189 561.7 0.27 1.8 γ 186Re 3.72 d β- 359.2 1069.5 0.9 5 γ 188Re 17.0 h β- 795.41 2120.4 3.5 10.8 γ 225Ac 9.92 d 4 α 5792 - 8375 < 0.1 β-, X, γ 213Bi 45.6 min α 5549 - 8375 < 0.1 β-, γ 211At 7.214 h α 5869 - 7450 < 0.1 X, γ

Chemical Emission type Energy and pathlenght: Image possibility properes for (Radiobiological Energy deposion in maer, (biodistribuon radiolabeling mechanism) ionisaon density following,

dosimetry,…) Compability with mAb Relave Biological Eﬀecveness (RBE) pharmacokinec and Linear Energy Transfer (LET) (residence me in tumor) Recent advances in RIT: Innovave radionuclides

Alpha or bêta minus ? β-

Ionisaon cluster β- track β- α

α emiers: 211At, 225Ac, 213Bi,…

Couturier O. et al. EJNM 2005. 5: 601-614 RBE

β- emiers: 131I, 90Y, 177Lu,…

LET (keV/μm) Recent advances in RIT: Innovave radionuclides

Trend 2016 09/27/2017 80 131I Total: 2878 items 115 - 90Y β Total: 1677 items

30 177Lu Total: 188 items

211At Total: 116 items 3 α

225Ac 213Bi Total: 49 items 3-4 items/year Total: 71 items 4-5 items/year Recent advances in RIT: Innovave radionuclides

α Eﬃcacy – Proof of concept 18 patients: 14 with multiform glioblastoma (GBM) 3 with anaplasic oligodendroglioma 1 with anaplasic astrocytoma 71 - 347 MBq of 81C6 - 211At Zalutsky at al. J Nucl Med (49)2008 30-38

thyroid

Liver Bladder

External probe 0,9 h 2,0 h 4,7 h 8,7 h 18,2 h 25,4 h Recent advances in RIT: Injecon way Large impact of biodistribuon Dose to Classical way: I.V. tumor Crical Pharmacokinec limit of mAb « Contrast » noon: organ Intratumoral penetraon Tumor/Healthy ssue rao

Alternave way: I.P. peritoneal carcinomatosis of colon cancer Used mainly for ovarian and colorectal cancer I.P. I.V.

Alternave way: Post-surgical cavity Beer accessibility to metastases Convecon Enhanced Delivery (CED) convecon

Validaon for pepde, future for mAb ? 1 clinical trial in lierature = acceptable diﬀusion safety proﬁle… Drug concentraon

Distance from injecon site Recent advances in RIT: Dose fraconaon approach

RIT principal limitaon: bone marrow / haematological toxicity

If only 1 injecon: dose limitaon to circumvent the toxicity…

Idea: use fraconated dose like external radiotherapy (increment of total dose) Principe: bone marrow regenerate faster than tumor cell

O O

NH NH

NH COO- NH COO-

N N

N COO- N COO- - - OOC N OOC N

N N

-OOC -OOC

2 weeks

740 MBq/m2 740 MBq/m2 Σ = 1480 MBq/m2 No toxicity 177 Lu-An-PSMA anbody 1480MBq/m2 1480MBq/m2 Σ = 2960 MBq/m2 Batra J.S. et al. J. Urol. 2016 Reversible myelosuppression

Single dose RIT : 2400-2600 MBq/m2 Fraconated dose RIT: 2960 MBq/m2 ≈ + 20 % Increase of overall survival Conclusion: Current opportunies Current status Haematologic tumors Solid tumors Clinical proof of eﬃcacy

Recent advances (radionuclides, mAb bioengineering, radiopharmaceucal development, protocol methodology, microenvironment targeng,…) : Major evoluon: Increase eﬃcacity Decrease toxicity (mainly haematological)

For tomorrow… Old R&D industrial anbodies (no intrinsic cytotoxicity but good vector properes) Radiochemistry and radiopharmacy development Scaffold proteins ? Liposomal formulaon (increase of the Specific Acvity) Microenviroment targeng (PD-L1 status ?) Contribuon of phenotypic imaging as companion diagnosc tool Combinaon between RIT and acve immunotherapy (renewal of abscopal effect ?) …

Preliminary clinical results appears promising… …personal medicine for RIT is almost a reality Thank you for your aenon