LA MEDICINA NUCLEAR EN LA INMUNOTERPIA ONCOLÓGICA “hacia el radioinmunoteragnóstico”

Joan Castell – Elisa Caballero HOSPITAL UNIVERSITARI VALL D’HEBRON HOSPITAL UNIVERSITARIO DOCTOR PESET

MEDICINA NUCLEAR E INMUNOTERAPIA XX JORNADA DE LA SOCIEDAD DE MEDICINA NUCLEAR E

IMAGEN MOLECULAR DE VALENCIA Y MURCIA 29 de Abril de 2016

SITUACIÓN ACTUAL:

Relación de la inmunoterapia con las técnicas MN en el seguimiento

de la inmunoterapia

IMAGEN DE DIANAS ESPECÍFICAS

RADIOINMUNOTERAPIA

Micrografía electrónica de barrido de un linfocito T humano (célula T) del sistema inmunitario de un donante sano. Fuente: National Institute of Allergy and Infectious Diseases (NIAID).

Douglas Hanahan, Robert A. Weinberg, Hallmarks of Cancer: The Next Generation, Cell, 2011, 646–674.

http://dx.doi.org/10.1016/j.cell.2011.02.013

Anticuerpos monoclonales: Avastin, Rituximab, Herceptin, Erbitux o Vectivix

Vacunas: Virus y Ca próstata (USA)

Transferencia celular adoptiva: cultivo/modificación linfocitos. Experimental en leucemia

Citoquinas: estimulan de forma global el sistema inmunológico, Interferon

Terapia con virus oncolíticos

Proteínas de control inmunológico: Ipilimumab (CTLA4) Anticuerpos PD1/PDL1: nivolumab, pembrolizumab…

TIPOS DE INMUNOTERAPIA

The programmed death 1 (PD-1) immune checkpoint pathway, which comprises the PD-1 T-cell coinhibitory receptor and its ligands PD-L1 and PD-L2 expressed on tumor and immune cells in the tumor microenvironment, mediates local immune resistance. Monoclonal antibodies blocking this pathway are active against advanced tumors of several different types, providing a “common denominator” for cancer therapy. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64

Proteínas de control inmunológico: Ipilimumab (CTLA4) Anticuerpos PD1/PDL1: nivolumab, pembrolizumab…

JAMA Oncol. 2015

Early increases in tumor size or the appearance of new lesions is classified as “progressive disease,” a term now synonymous with treatment failure.

AJR:197, August 2011

Nghiem PT, et al. April 19, 2016, NEJM.org. DOI: 10.1056/NEJMoa1603702

Response to Pembrolizumab in a Patient with Stage IV Merkel-Cell Carcinoma

The primary end point was the objective response rate measured according to RECIST, version 1.1 Secondary end points were progression-free survival, overall survival, and duration of response

26 patients (OR 56%) 4 CR 10 PR RPFS 6m 67%

Clin Cancer Res 2009

Four response patterns observed in advanced melanoma patients treated with ipilimumab (CTLA-4 antibody).

Type A: reduction in size of baseline lesions with no new lesions Type B, stable disease with no significant change in the size of the baseline lesions that may or may not be followed by a slow, steady decline in tumor size Type C, initial increase in tumor burden followed by response Type D, reduction in total tumor burden in spite of the appearance of new lesions

Clin Cancer Res 2009

Type B

When new lesions are present on a postbaseline restaging assessment, patients are not considered to have progressive disease (immune-related progressive disease) if the total tumor burden has not increased by more than 25%. The first posttreatment scan should be obtained at 12 weeks, followed by subsequent scans every 8 weeks. However, in patients who have progressive disease (immune-related progressive disease) on imaging, this finding must be confirmed with a second scan at least 4 weeks later so that a type C response pattern may be identified

Type C response to ipilimumab therapy

Type C response to ipilimumab therapy

Baseline CT 12 weeks CT CT 24 weeks CT CT

O’Reagan KN, AJR 2011

Type D response to ipilimumab therapy

Baseline CT 12 weeks CT CT 24 weeks CT CT

O’Reagan KN, AJR 2011 Ipilimumab induced colitis

Major toxicity Autoimmune enterocolitis, pericolonic inflammatory changes, free fluid and occasionally intestinal perforation Autoimmune hypophysitis, 5% Ipilimumab-induced hepatitis, rare

The “state-of-the-art”: functional imaging in oncology

13

Diagnosis and staging Therapy selection Optimization of intervention

• Enriched tumor localisation

• Cancer metabolism / Phenotypic Expression

• Tumor metabolic staging

• Patient matching

• Disease matching • Track treatment response

• PERCIST (PET Response Criteria in Solid Tumors)

• Guide radiotherapy

• Guide surgery

STRUCTURAL IMAGING

Tumor location/staging

13

FUNCTIONAL IMAGING

• Tiene en cuenta cambios en valor de SUV corregido por masa magra (SUL) • La respuesta tumoral en PET es una variable continua y tiempo-dependiente • De forma análoga al RECIST, habla de RC, RP, PE, EE

RC Desaparición de todas las lesiones activas metabólicamente

RP Disminución ≥ 30% en el pico SUL entre las lesiones más intensas pre y post-tto, con al menos una caída del SUL del 0.8 unidades, y sin nuevas lesiones

PE - Aumento ≥ 30% en el pico SUL entre las lesiones más intensas pre y post-tto, con un incremento > 0.8 unidades

- Aparición de nuevas lesiones hipermetabólicas

EE No cumple ninguno de los criterios anteriores

Wahl. JNM 2009

JNM 2009

18F-FDG PET-TC en evaluación de respuesta

• La actividad metabólica precede a la reducción de tamaño

• Respuesta metabólica precoz es predictora de eficacia terapéutica

• Masa no siempre significa tumor

Pre-tto Post-tto

Tratamiento antiangiogénico

Elisa Caballero Calabuig, 2016

FDG PET/CT readings can be confounded by the presence of inflammatory cells FDG can mimic tumor FDG uptake in lymph nodes Mild FDG uptake in many lymph nodes after immune modulation therapy, then the uptake is more likely due to inflammation than to tumor We usually recommend follow-up PET/CT within 1–2 months to ensure that it is inflammatory uptake Immunomodulation therapy, which potentiates T lymphocytes, is known to produce a high rate (up to 70%) of adverse immune-related reactions, including colitis, dermatitis, hypophysitis, arthritis, and thyroiditis

AJR 2015; 205:259–270 Johns Hopkins School of Medicine, Baltimore

• 22 pacientes • MM irresecable (no cerebrales) • Ipilimumab iv 3 mg/kg x 4 • 16 pretratados • 18F-FDG PET basal y tras 2º y 4º ciclos

In conclusion, our preliminary data show the high value of 18F-FDG PET/CT performed after two cycles of ipilimumab therapy in predicting the final treatment outcome in patients finally classified with PMD and SMD (18 of 20 patients, 90% correctly classified). These patients represented the majority of patients in the present study. In particular, the number of new lesions was predictive of progressive disease

before ipilimumab treatment

first follow-up PET/CT

end of treatment

22 pts, unresectable metastatic melanoma 15 patients progressive metabolic disease (PMD) 5 pts, stable metabolic disease (SMD) 2 pts, partial metabolic response (PMR) * Both patients with PMR showed pseudoprogression after the second cycle and were therefore wrongly classified

2012

Dianas

Sharma P. The PET Clinics 2015

2. RADIOFÁRMACOS PET DIANAS ESPECÍFICAS

Representative molecular PET images of patient with HER2-positive breast cancer. Geraldine Gebhart et al.

J Nucl Med 2016;57:81S-88S

(c) Copyright 2014 SNMMI; all rights reserved

18F-FDG 89Zr-trastuzumab

Trastuzumab Humanized monoclonal antibody against Human Epidermal Growth Factor Receptor 2 (HER2)

Uptake of 68Ga-HER2-Nanobody in primary breast carcinoma (thick arrow) and invaded lymph node (thin

arrow) with high HER2 expression. Geraldine Gebhart et al. J Nucl Med 2016;57:81S-88S

(c) Copyright 2014 SNMMI; all rights reserved

68Ga-HER2-Nanobody in primary breast carcinoma

J Nucl Med 2016; 57:96–102

The CD30-specific antibody–drug conjugate, brentuximab vedotin, is approved for the treatment of relapsed, refractory Hodgkin lymphomas and systemic anaplastic large T-cell lymphomas. CD30 expression varies among different types of lymphoma and can also change during the course of treatment, companion diagnostic imaging of CD30 could be a valuable tool in optimizing patient-specific brentuximab vedotin treatment regimens.

Complementary approaches to overcome tumor-induced tolerance.

Blockade of CTLA-4 on potential effector cells in secondary lymphoid organs is combined with different strategies, such as chemotherapy, radiation, surgery, cryoablation, vaccination, adoptive T cell therapy, cytokine therapy, and antibody blockade of additional negative (i.e., PD-1, LAG-3, Tim-3) or positive (i.e., CD137) regulatory receptors to achieve synergistic anti-tumor effects.

Grosso J, Cancer Immunity 2013

3. RADIOINMUNOTERAPIA

INMUNOCOMPLEJOS MARCADOS CON EMISORES : 213Bi, 211At, 225Ac : 131I, 177Lu, 90Y DNL™ conjugates binding: CEA (TF2) CD20 (TF4) Mucin antigen expressed by pancreatic tumors (TF10) Trop-2antigen(TF12)

PRIMERA RIT yttrium-90 ibritumomab tiuxetan (Zevalin) iodine-131 tositumomab (Bexxar)

Efecto biológico

• Salida de electrones de la corteza atómica

• Aparición de iones y radicales libres

• Cambios moleculares especialmente del ADN – Daño cromosómico

– Trastorno del crecimiento celular

– Apoptosis

– Muerte celular

Semin Nucl Med 46; 2016

CROSSFIRE

Unconjugated MoAb Radiolabelled MoAb

El rango de penetración de estas partículas es generalmente mayor que la partículas alfa pero poseen una menor LET

• 131I: emisor gamma (360 KeV)

emisor 0.606 MeV

• 177Lu: ß de 0.497 MeV : 113 keV / 208 keV

• 90Y: emisor (2.3 MeV)

Penetración de tejidos biológicos desde 3,5 a 11 mm (5mm promedio)

Emisores

INDICACIONES ENF. ENDOCRINAS Tiroides RSS: análogos de la somatostatina LINFOMAS (unido a MoAb) Hibritumomab (rituximab)

MoAb en otros tumores (ensayos clínicos) Microesferas (radioembolizacion mets hepáticas)

• Anticuerpo monoclonal murino anti-CD20 unido al Ytrio-90 mediante Tiuxetan (enlace covalente muy estable)

• Reconoce específicamente el antígeno CD20 de los linfocitos B normales y malignos

• No se fija a la linea celular progenitora de linfocitos B, haciendo posible la recuperación posterior

RATIONAL

Lymphoma cells are sensitive to radiation.

Radioimmunotherapy (RIT) combines the selectivity of anti-CD20 immunotherapy with an attached radioisotope, making it possible to deliver radiation to within the tumor

INDICATIONS CD20+ F-NHL B-cell lymphomas (in particular, indolent Subtypes) Consolidation after first-line chemotherapy for patients with a CR or PR

Zevalin está indicado en adultos. Zevalin marcado con itrio-90 (90Y) está indicado como tratamiento de consolidación después de la inducción de la remisión en pacientes con linfoma folicular no tratados anteriormente. Zevalin marcado con itrio-90 (90Y) está indicado para el tratamiento de pacientes adultos con linfoma no Hodgkin (LNH) folicular de células B CD20+ en recaída o refractario a rituximab.

INDICACIÓN EN FICHA TÉCNICA

• Radiación corto alcance

• Sin ingreso hospitalario

• No irradiación significativa a otras personas

• Eliminación urinaria en 7 días del 7.3 +/- 3.2% de la actividad administrada

CONDICIONES DE USO ASISTENCIAL

Toxicidad aguda

• No hematológica

• unión antiC anti-CD20 a células B circulantes

• activación complemento

• liberación citoquinas

• ocasionalmente taquicardia, fiebre, sudoración, prurito, hipotensión, náuseas

• Basal-30 min: TA, FC, Temperatura

Toxicidad y efectos adversos

Toxicidad subaguda

• Mielosupresión tardía

• Toxicidad hematológica muy frecuente, pero transitoria y reversible

• En función grado afectación previa MO

• Inicio sem 3-4, nadir 6-7, recup 3 meses

• Trombopenia

• En menor grado, neutropenia y anemia

• Estrecho control hematológico

• Infecciones inespecíficas, hemorragias

Otras consideraciones

• Mayor toxicidad hematológica en pacientes que recibieron tratamiento previo con fludarabina

• Posibilidad desarrollo anticuerpos HAMA (1-2 %) contra los anticuerpos murinos (determinación-posible influencia en tratamientos posteriores)

• Buena tolerancia en pacientes hasta 85 a

Efectos adversos tardíos

• Síndromes mielodisplásicos

• Leucemia mieloide aguda

Zevalin at relapsed or refractory patients

Long-term Responses in Patients with Recurring or Refractory B-

Cell Non-Hodgkin Lymphoma Treated with Yttium 90

Ibritumomab Tiuxetan

Witzig et al. May 2007

Review four Clinical Trials at 30 centers in United States

A single dose of ZEVALIN

Follow Up : 53.5 month

Patients Characteristics 70 % Third line or more of treatment

44 % Fourth line or more of treatment

No response to last therapy 52%

Bulky desease > 5cm 56%

Pretreatment characteristics predictive of LTR to Zevalin:

Nonbulky disease (<5 cm)

Stage I or II disease

Pretreatment characteristics NOT predictive of LTR to Zevalin:

Response to last previous therapy

Patients age

Number of previous therapies

CR/CRu best predictor of LTR to Zevalin

Conclusions of Zevalin Long-Term Responses and Safety

Well Tolerated

Adverse events primarily hematologic and reversible

Incidence of severi bleeding 2%

Platelet transfusion 20% - Red Blood Cell Transfusion 22%

Rare cases of MDS, within expected rate in heavily pretreated population

Causes of death and Incidence of 2nd malignances

Secondary Malignancies, n (%)

Control

(n=202)

90Y-Ibritumomab

(n=207)

Total

(N=409)

Overall total (P = 0.086) 14 (7) 26 (13) 40 (10)

AML/MDS 1* (0.5) 7 (3) 8 (2)

Pancreas − 3 (1) 3 (1)

Prostate − 3 (1) 3 (1)

Other 13 (6) 13 (6) 26 (6)

• Median time from study registration to incidence of secondary AML/MDS was 4.6 years for Control vs 4.8 years for 90Y-Ibritumomab.

• No additional late toxicities or congenital malformations were detected.

Causes of Death Control, n (%) 90Y-Ibritumomab, n (%)

n = 202 n = 207

Progressive disease 22 (11) 13 (6)

Secondary malignancy 4 (2) 8 (4)

Other 6 (3) 7 (3)

Total Deaths 32 (16) 28 (13)

Z-BEAM: a standard conditioning?

Conditioning Regimen in 30 publications

More than 1000 patients

Conditioning in DLBCL, FL, MCL, LT

Large series prospectives = Z-BEAM 1 & 2 LYSA ( Follicular and DLBCL)

All publications between BEAM and Z-BEAM report an advantage in OS without increase toxicity for Z-BEAM

45

BCNU: 300mg/m2 (2 hours) day -6 VP-16: 200mg/m2/day (2 hours) days -5 to -2

ARA-C: 200mg/m2/12 hours (2 hours) days -5 to -2 Melafalan: 140mg/m2/day (15 min.) day -1

Z-BEAM Regimen

Auger-Quittet S, Cancer Medicine 2014

Z-BEAM: OS improvement

0.000

0.250

0.500

0.750

1.000

0.0 12.0 24.0 36.0 48.0 60.0 72.0

months

over

all s

urvi

val

Z-BEAM (20/22)

BEAM

(13/21)

2 years OS

91% vs 67% (p=0.05)

Wondergem – BJH 2011 Shimoni – Cancer 2012

2 years OS

90% vs 65% (p=0.02)

Krishnan – BBMT 2012

(n = 46)

(n = 46)

4 years OS

81% vs 52% (p=0.01)

Anti-CD33 RIT for Treatment of Acute Myeloid Leukemia Anti-CD45 RIT for Treatment of Acute Leukemia and Myelodysplasia Anti-CD22 RIT for Treatment of Acute Lymphoid Leukemia

RIT EN LEUCEMIA

RIT EN TUMORES SÓLIDOS

Strategies have been trialed clinically and preclinically in search to enhance the clinical response to RIT drugs in solid tumors: (1) Fractionated dose regimen (multidose) therapy (2) Combinations of RIT with radiosensitizing chemotherapy (3) Pretargeting RIT (pRIT) strategies (4) RIT with a personalized cocktail of radiolabeled antibodies or

radionuclides

Pasternack JB, Domogauer JD, Khullar A, et al: The advantage of antibody cocktails for targeted alpha therapy depends on specific activity. J Nucl Med 2014 Karacay H, Sharkey RM, Gold DV, et al: Pretargeted radioimmunotherapy of pancreatic cancer xenografts:TF10-90Y-IMP-288 alone and combined with gemcitabine. J Nucl Med 2009 van Rij CM, Lutje S, Frielink C,et al: Pretargeted immuno-PET and Radioimmunotherapy of prostate cancer with an anti-TROP-2xanti-HSG Bispecific antibody. Eur J Nucl Med Mol Imaging 2013

Phase 3 Trial of 90Y-Clivatuzumab Tetraxetan & Gemcitabine vs Placebo & Gemcitabine in Metastatic Pancreatic Cancer (PANCRIT®-1) In patients who have progressed on at least 2 prior therapies for metastatic cancer (1 of which was a gemcitabine-containing regimen). This study has been terminated. (The DSMB conducted an interim analysis on overall survival, which showed that the treatment arm did not demonstrate a sufficient improvement in OS vs. placebo.)

188Re-6D2 mAb. Patient from phase Ia study 188-Rhenium-labeled antibody to melanin

18FDG PET/CT 10 days before the study

SPECT/CT of 188Re-6D2 mAb

2H

8H

24H

Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

Klein M, Journal of Skin Cancer 2013

LIMITACIONES DE LA RIT EN TUMORES SÓLIDOS

Pathophysiologicalc hanges in the tumor: (1) The natural heterogeneity of the target antigen density causing problems delivering

enough radionuclide or antibody load to tumors

(2) The binding site barrier, which occurs when alow dose of labeled antibody is administered or when a high-affinity antibody binds strongly to the tumor antigens at the tumor periphery and gets stuck, resulting in a low-administered dose to the tumor

(3) The non uniformity of tumor vascularization and capillary permeabilityt hat can lead to elevated interstitial fluid pressure inside the tumor

(4) Problems in delivering high-enough absorbed dose to the tumor while avoiding nontargeted organs (dose-limiting toxicity to normal tissues like bone marrow)

(5) Targeting the micrometastases outside the radiation field

Semin Nucl Med 2016

Antibody-based recognition systems: “bispecific” antibodies and radiolabeled haptens The concept of pretargeting with the Affinity Enhancement System

First Step: A bispecific antibody, designed to bind by one arm a tumor antigen (e.g., carcinomembryonic antigen) and by the other a hapten (e.g., the indium-DTPA complex or the HSG -histamine-succinyl-glycinepseudo-peptide-), is injected first. It distributes in the body and binds the tumor. Second Step: After an interval of several hours to a few days, the bispecific antibody has cleared from the circulation and the radiolabeled bivalent hapten is injected. It binds rapidly to the tumor. At the tumor cell surface, hapten bivalency induces cooperativity that results in very slow release. Immuno-positron emission tomography: shedding light on clinical antibody therapy. van Dongen, G. A., and Vosjan,M. J. Cancer Biother Radiopharm 2010 Pretargetedimmuno-PET and radioimmunotherapy of prostate cáncer with an anti-TROP-2xanti-HSG bispecific antibody. van Rij C. Eur J Nucl Med Mol Imaging 2013

Pretargeted immuno-PET

120 nmol of TF2 (CEA) and 6 nmol of 68Ga-IMP-288 at 30 h in a patient with a relapse of Medullary Thyroid Carcinoma

Kraeber-Bodéré F ,et al JNM 2006

120 nmol of TF2 (CEA) and 6 nmol of 68Ga-IMP-288 at 42 h in a patient with a relapse of MTC.

18F-DOPA

Kraeber-Bodéré, F et al JNM 2006

Pretargeted immuno-PET recorded after injection of 120 nmol of TF2 (CEA) and 3 nmol of 68Ga-IMP-288 at 30 h in a patient with metastatic breast carcinoma

FDG-PET Kraeber-Bodéré, F et al Front Pharmacol 2015

68Ga-IMP-288

EN RESUMEN Las técnicas de diagnóstico y tratamiento metabólico relacionadas con la inmunoterapia requeriran de nuevos enfoques de interpretación y definición de estrategias teranósticas El reto actual está en llevar a la práctica clínica las herramientas necesarias que permitan aplicar las técnicas de imagen y su interpretación en paralelo al desarrollo famacológico. La RIT está en fase de optimización para conseguir una mayor irradiación tumoral y menor toxicidad en tejidos sanos. La mayor efectividad de la RIT se desarrollará en la combinación con tratamientos que actuen sinérgica y personalizadamente sobre las diferentes dianas específicas (vías de señalización) de cada tumor La mayor parte de los RIT son de aplicación ambulatoria con bajos requerimientos de Radioprotección y con eficientes balances costo-eficacia