General overview of radioimmunotherapy of solid ...

Review General overview of radioimmunotherapy of solid tumors Radioimmunotherapy (RIT) represents an attractive tool for the treatment of local and/or diffuse tumors with radiation. In RIT, cytotoxic radionuclides are delivered by monoclonal antibodies that specifically target tumor-associated antigens or the tumor microenvironment. While RIT has been successfully employed for the treatment of lymphoma, mostly with radiolabeled antibodies against CD20 (Bexxar® ; Corixa Corp., WA, USA and Zevalin® ; Biogen Idec Inc., CA, USA and Schering AG, Berlin, Germany), its use in solid tumors is more challenging and, so far, few trials have progressed beyond Phase II. This review provides an update on antibody–radionuclide conjugates and their use in RIT. It also discusses possible optimization strategies to improve the clinical response by considering biological, radiobiological and physical features. Keywords: cancer n monoclonal antibody n radiobiology n radioimmunotherapy n radionuclide n solid tumor

Radiation is a powerful tool for controlling the growth of or killing cancer cells. Whereas conventional external-beam radiotherapy is dedicated to localized disease, radioimmunotherapy (RIT) offers the possibility of treating both localized and diffuse tumors. RIT is used successfully for the treatment of hematological malignancies; on the other hand, solid tumors constitute a bigger challenge as they appear to be more radioresistant. Optimization approaches are currently developed by taking into account biological, radiobiological or physical features to significantly improve the clinical response to RIT in solid tumors.

and Schering AG, Berlin, Germany; 90Y‑ibritumomab tiuxetan) in 2002 and Bexxar® (Corixa Corp., WA, USA; 131I‑tositumomab) in 2003, were approved by the US FDA for the treatment of non-Hodgkin’s lymphoma (NHL). This was a landmark in the history of therapeutic radiolabeled mAbs; however, few other radio labeled antibodies have progressed beyond early Phase II trials, particularly in the case of RIT for solid tumors, which are more radioresistant than hematological malignancies. This review provides an update on mAb–radio nuclide conjugates and their use in RIT of solid tumors. It also summarizes the possible optimization approaches to obtaining significant clinical responses in solid tumors.

Background Conventional external beam radioimmuno therapy (EBRT) is included in approximately 50% of cancer treatment protocols and relies on the acute deposition of energy within sensitive biological targets to produce nonrepairable damage. This makes radiation a powerful tool for tumor cell sterilization. While conventional EBRT is dedicated to localized disease, radio immunotherapy (RIT) offers the possibility of treating both localized and diffuse tumors with acceptable exposure of healthy tissues to radiation and limited toxicity. In RIT, unstable radionuclides (a, b or Auger electron emitters) are delivered by monoclonal antibodies (mAbs) that target tumor-associated antigens (TAAs) or stromal components. Much research has been carried out and two radiolabeled anti-CD20 mAbs, Zevalin® (Biogen Idec Inc., CA, USA

Clinical RIT of hematological cancers The first clinical trials in 1988 focused on the treatment of hematological malignancies using 131I‑labeled or 67Cu‑labeled Lym-1 (anti-HLA‑DR) mAbs [1] . They were followed in 1993 by the first successful trial using high activities of 131I‑labeled anti-CD20 mAbs in patients with NHL [2] . In the same year, Kaminski et al. reported the complete remission of four out of nine patients treated with nonmyeloablative activities of 131I‑labeled anti-B1 (anti-CD20) mAbs [3] . It took until 2002–2003 before two anti-CD20 mAbs were approved by the FDA (Zevalin®, 90Y‑ibritumomab tiuxetan; Bexxar®, 131I–tositumomab) for the treatment of relapsed or refractory low-grade, follicular or

10.2217/IMT.13.34 © 2013 Future Medicine Ltd

Immunotherapy (2013) 5(5), 467–487

Isabelle NavarroTeulon1,2,3,4, Catherine Lozza1,2,3,4, André Pèlegrin1,2,3,4, Eric Vivès1,2,3,4 & Jean-Pierre Pouget*1,2,3,4 IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France 2 INSERM, U896, Montpellier, F-34298, France 3 Université Montpellier1, Montpellier, F-34298, France 4 Institut régional du Cancer de Montpellier, ICM, Montpellier, F-34298, France *Author for correspondence: [email protected] 1

Clinical RIT trials

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transformed B-cell lymphoma [4] . The complete response rate with anti-CD20 mAbs ranged between 20 and 49%, the overall response rate from 60 to 80% with mild toxicity and the superiority of labeled versus unlabeled mAbs was demonstrated in patients with recurrent follicular lymphoma [5] . Other cell-surface antigens targeted by RIT in hematological malignancies have been reviewed elsewhere [6,7] . Clinical RIT of solid tumors RIT is used successfully for hematological disease; conversely, solid tumors constitute a bigger challenge and only few clinical trials went beyond Phase II (Table 1) . More than 60 clinical RIT studies have been carried out since 1990 and approximately 15 solid TAAs have been targeted in 12 cancer types, including breast, ovarian, colorectal, prostate, kidney, pancreatic, thyroid and brain cancer (Table 1 & Box 1) . Most of these studies were Phase I/II trials and significant clinical responses were observed, for example, in patients with advanced breast cancer treated with 131I‑ChL6 [8] or anti-MUC1 (BrE-3, m170) 90Y‑mAbs [9,10] . However, few clinical trials have progressed to Phase III. The first one concerned the use of 90Y‑labeled HMFG-1 (anti-MUC1) mAbs in ovarian carcinoma [11] , while the second is currently testing 131I‑labeled 81C6 (antitenascin) mAbs for the treatment of glioblastoma multi forme [12] . This very limited number of Phase III clinical trials could be due to several reasons, including: The high cost of RIT trials; The limited access to RIT; Its use mainly for secondary malignancies and in an adjuvant setting; The restricted eligibility criteria, leading to long inclusion delays in studies for which a large number of patients is recommended. The development and optimization (i.e., antibody affinity modulation, choice of the optimal radionuclide, preclinical evaluation and delivery improvement) of new antibody–radionuclide conjugates is very slow. Thus, most of the solid TA As that have recently been or are currently evaluated in RIT clinical trials are not novel solid tumor targets (Table 1) . Indeed, the literature published in the past 2 years mainly concerns solid TAAs that have been investigated during the last decades (Table 1) [13–22] . 468

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Strategies for optimizing RIT for solid tumors In contrast to hematological malignancies, solid tumors are less sensitive to radiation. Moreover, the slow diffusion rate and the long distance of diffusion in poorly vascularized tumors are the main reasons for the insufficient tumor localization of radioimmunoconjugates and could explain the limited clinical success of RIT for solid tumors. Thus, many challenges remain before RIT might become an effective therapeutic approach for solid tumors. In the next section, we will discuss the different strategies to improve its success rate based on the results of previous RIT trials. mAbs for radionuclide therapy For a long time, much effort was focused on the development of the best targeting vectors. The first therapeutic antibodies were polyclonal until the invention of hybridoma technology by Kölher and Milstein in the 1970s [23] . This technology allowed the generation of highly specific mAbs against human TAAs (mainly tumor receptors). The availability of large amounts of purified, well-standardized mAb preparations suitable for therapy accelerated their use by clinical oncologists. However, early trials with full-length mouse mAbs were disappointing owing to their low efficacy and rapid clearance [24–26] . Indeed, mouse antibodies induce human antiglobin antibody responses that can lead to enhanced elimination in case of repeated administrations, thereby limiting the frequency of administration and thus their efficacy [27] . These limitations were overcome by the development of chimeric [28,29] and humanized [30] mAbs that reduce the immunogenicity and increase the therapeutic efficiency of mAbs [30,31] . Fully human antibodies eliminate the problems associated with the human antimouse antibody immune response and allow repeated injections of mAbs in fractionated dose RIT regimens [32] . The development of phage display technology [33] and the production of transgenic mice genetically engineered to produce human-like antibodies [34] led to a substantial increase in the generation and clinical study of human mAbs [35,36] . At least 31 human, humanized and chimeric antibodies have been approved for clinical use in a variety of indications (13 for cancer therapy) and many more are under investigation [36–38] . Choosing the most appropriate isotope The choice of the best vector is generally followed by the selection of a radionuclide (Table 2) . future science group

General overview of radioimmunotherapy of solid tumors

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Table 1. Clinical studies on radioimmunotherapy for solid tumors. Isotope/antibody

Clinical phase

Route

Cancer type

Ref.

I‑A5B7 and -CA4P

I

iv.

GC

[176]

I‑F6 F(ab’)2

I

iv.

CC

[177]

I‑BsmAb-hMN14-734

I

iv. (pRIT)

CEAexp

Y‑hMN14

I

iv. (hdRIT)

MTC

CEA 131 131 131 90 90

[93] [23] [178–180] [181]

Y‑cT.84.66

I

iv.

CEAexp BC, CC

I‑MN14 F(ab’)2

I

iv.

MTC

I‑COL-1

I

iv.

GIM

[183]

131 131

[182]

I‑35/B7-25/F6

I

iv.

CC

[184]

I CIGB-M3

I

iv.

CC

[15]

I‑KAb201

I/II

iv., IA

PC

[185]

I‑A5B7hDFM

I/II

iv.

CC

[186]

I‑MN14 F(ab’)2

I/II

iv.

MTC

[187]

I‑hMN14

I/II

iv.

OC

[188]

I‑NP4 (IMMU-4)

I/II

iv.

CEAexp

[189]

I‑BsmAb-F6-734 or 131I‑hMN14-734

II

iv. (pRIT)

MTC

I‑hMN14

II

iv.

CC

I‑BsmAb-hMN14-734

II

iv. (pRIT)

MTC

131

131 ‑ 131 131 131 131 131 131 131 131

[95] [190,191] [16]

TAG-72 90

Y‑hCC49DCh2(IDEC-159)

I

iv.

CC

[111]

90

Y‑Biot/-CC49-(scFv)4-strept

I

iv. (pRIT)

GC

[95]

Lu-CC49 or Y‑CC49

I

ip.

OC

[110]

Y‑CC49

I

iv. (hdRIT) iv.

GC NSCLC

I‑cB72.3

I

iv. (fRIT)

CC

[194]

II

iv.

PC

[195]

II

iv.

CC

[196]

177 90

90

131

I‑CC49

131 90

Y‑CC49 and

I‑COL-1

131

[67,192] [193]

A33 124

I‑huA33

Dosimetry

iv.

CC

[13]

124

I‑huA33

PET/CT

iv.

CC

[14]

I

iv.

CC

[197]

I

iv.

CC

[198]

I‑huA33

131

I‑huA33 and

131

125

I‑huA33

I/ I‑A33

I

iv.

CC

[199]

I‑A33

I/II

iv.

CC

[61]

Dosimetry

iv.

RCC

[13]

131 125 125

G250 124

I‑cG250

I‑cG250

I

iv. (fRIT)

RCC

[200]

I‑mG250

I

iv.

RCC

[201]

131 131

BC: Breast cancer; Biot: Biotin; BsmAb: Bi-specific monoclonal antibody; BT: Brain tumor; CC: Colorectal cancer; CEAexp: CEA-expressing tumors; CT: Computed tomography; DOTA: Tetra-azacyclododecanetetra acetic acid; ED-B: Extradomain B; fRIT: Fractionated radioimmunotherapy; GC: Gastric cancer; GIM: Gastrointestinal malignancies; GL: Glioma; HCC: Hepatocellular carcinoma; hdRIT: High-dose radioimmunotherapy; HNC: Head and neck carcinoma; IA: Intra-arterial; IMRT: Intensity-modulated radiotherapy; ip.: Intraperitoneal; IRC: Intraresection cavity; iv.: Intravenous; OC: Ovarian cancer; M: Melanoma; MTC: Medullar thyroid cancer; NSCLC: Non-small-cell lung cancer; PC: Prostate cancer; pRIT: Pretargeted radioimmunotherapy; RCC: Renal cell carcinoma; Strept: Streptavidin. Adapted with permission from [6].

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Table 1. Clinical studies on radioimmunotherapy for solid tumors (cont.). Isotope/antibody

Clinical phase

Route

Cancer type

Ref.

Lu-cG250

I

iv.

RCC

[18,19]

I‑mG250

I/II

iv.

RCC

[202]

I‑cG250

II

iv.

RCC

[203]

I

Local

GL

[204]

I/II

iv. (pRIT)

GL

[205]

At-ch81C6

II

IRC

BT

[111]

I‑m81C6

II

IRC

GL, BT

[12,112]

[10]

G250 (cont.) 177 131 131

TN-C 90

Y‑BC4

Biot-BC4/ 90Y‑DOTA-Biot 211

131

MUC1 90

Y‑m170

I

iv. (hdRIT)

PC, BC

90

Y‑hPAM4

I

iv. (fRIT)

GC

[20,21]

90

Y‑m170

II

iv. (pRIT)

PC

[91]

I/II

iv.

GL

[60]

EGF receptor I‑425

125 125

I‑425

II

iv.

GL

[206]

125

I‑425

II

iv.

GL

[207]

IMRT/h425

II

IMRT

HNC

I/II

ip.

OC

[208]

[17]

HMFG 1,2 90 90

Y‑HMFG-1 Y‑HMFG-1

III

ip.

OC

[11,108]

I

iv.

PC

[209,210]

I

iv. (fRIT)

PC

[211,212]

I

iv.

CC

[213]

I/II

iv.

HCC

[154]

I

IT

BC

[214]

I

ip.

OC

[48] )

II

iv. (pRIT)

CC

[79]

I

iv.

NSCLC

I

iv. (pRIT)

M

PSMA In-huJ591

111

177

Lu-huJ591 or Y‑huJ591 90

Nucleus 125

I‑c17-1A

Hab18/CD147 I‑Hab18 F(ab’)2

131

GD2 I‑3F8

131

NaPi2b At-MX35 F(ab’)2

211

EpCAM NR-LU-10-Strept and 90Y‑DOTA-Biot ED‑B fibronectin I‑L19SIP

131

[102]

NG2/MCSP 213

Bi-cDTPA-9.2.27

[22]

BC: Breast cancer; Biot: Biotin; BsmAb: Bi-specific monoclonal antibody; BT: Brain tumor; CC: Colorectal cancer; CEAexp: CEA-expressing tumors; CT: Computed tomography; DOTA: Tetra-azacyclododecanetetra acetic acid; ED-B: Extradomain B; fRIT: Fractionated radioimmunotherapy; GC: Gastric cancer; GIM: Gastrointestinal malignancies; GL: Glioma; HCC: Hepatocellular carcinoma; hdRIT: High-dose radioimmunotherapy; HNC: Head and neck carcinoma; IA: Intra-arterial; IMRT: Intensity-modulated radiotherapy; ip.: Intraperitoneal; IRC: Intraresection cavity; iv.: Intravenous; OC: Ovarian cancer; M: Melanoma; MTC: Medullar thyroid cancer; NSCLC: Non-small-cell lung cancer; PC: Prostate cancer; pRIT: Pretargeted radioimmunotherapy; RCC: Renal cell carcinoma; Strept: Streptavidin. Adapted with permission from [6].

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General overview of radioimmunotherapy of solid tumors

This is mainly based on practical considerations (e.g., cost, availability, type of radio labeling techniques and ease of use), emission type/linear energy transfer (LET) and physical half-life (T1/2Phys ) (Table 2) [39] . The radionuclide’s T1/2Phys must match the mAb pharmacokinetics as much as possible in order to deliver the highest absorbed dose to the tumor after injection. It also needs to be compatible with clinical applications and, thus, the time required for shipping the radionuclide from the production site to the hospital and for mAb labeling, as well as issues related to radiation protection and waste management, have to be taken into account. In addition, different T1/2Physwill produce different dose rates (shorter T1/2Phys means higher dose rate) with different biological effects. LET corresponds to the energy released by the radiation per unit of distance (keV/µm) and radionuclides are arbitrarily divided into low, intermediate and high LET radiation emitters (Table 2) . A variety of radionuclides have thus been considered for RIT, but the most commonly used in human clinical trials are radionuclides that emit low LET radiations (0.2 keV/µm), such as 131I and 90Y, followed by 177 Lu, 188Re, 186Re, and 67Cu. Low LET radiation suitable for therapy includes b particles (negatively charged electrons) and internal conversion electrons. Low LET radiations produce sparse ionization and individual DNA lesions, such as single- and double-strand DNA breaks, DNA base damage and DNA–protein cross-links that are easily repairable (sublethal damage). b-particles and internal conversion electrons have intermediate energy (30 keV–2.3 MeV), but have a long range in tissues (0.05–12 mm) that leads to an extensive ‘cross-fire’ effect (Figure 1) [40,41] . This effect is particularly attractive when it concerns relatively inaccessible or antigen-negative cells that cannot be reached by radiolabeled mAbs due to their heterogeneous distribution. However, in LET, long path length can also be involved in bone marrow toxicity. Theoretically, b-emitters are more suitable for bulky tumors because in minimal disease, most of the energy would be deposited outside the tumor [42,43] . A mathematical model was used to demonstrate that the optimum size for curability, assuming a homogeneous radionuclide distribution, was 34 mm for 90Y and 3.4 mm for 131I [43] . However, in reality, the distribution of radiolabeled molecules in healthy organs and tumors is generally nonuniform and the dose calculation must take into account such heterogeneity [44,45] . As it is now recognized that RIT of solid tumors future science group

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should be preferentially dedicated to therapy of small-volume disease, low-energy b-emitters, such as 177Lu (T1/2Phys = 6.7 days; maximum energy = 497 keV with a range of mm in tissue), might be preferable for RIT than highenergy b-emitting radionuclides to limit bone marrow toxicity. However, the main weakness of low LET radiations is their low ionizing power. Conversely, a-particles are much more ionizing along their track than b-particles. They are produced by radionuclides of high atomic number, including 225Ac, 213Bi, 212Bi and 211At, and can be eluted from 212Pb/212Bi and 225Ac/213Bi generators, or produced by cyclotrons. These isotopes have already been used for treating patients with hematological malignancies [46,47] , solid tumors and brain, gastric, colorectal and ovarian cancer [48,49] , and for targeting tumor vascular antigens [50] . a-particles have high energy (5–9 MeV) and an intermediate path length in biological tissues (50–100 µm) that corresponds to the diameter of several cells [51] . They are high-linear energy transfer radiations (50–230 keV/µm) and produce clusters of damage along their track independently of the dose rate and tissue oxygenation. The term ‘cluster of lesions’ defines two or more lesions caused by a single radiation track within one to two helical turns of DNA. They include double-strand breaks with associated base lesions or abasic sites, and nondouble strand break clusters that include base lesions, abasic sites, and single-strand breaks. These lesions Box 1. Main tumor-associated antigens. A33: a transmembrane glycoprotein that is expressed in colorectal cancer cells CEA: the carcinoembryonic antigen that is strongly expressed in epithelial tumors from the digestive tract: colorectal, gastric and pancreatic cancer ED‑B: fibronectin (oncofetal extradomain-B containing fibronectin) that is expressed in a variety of human cancers EGFR: EGF receptor, a member of the HER family that is involved in many tumor cell growth and differentiation pathways, and is expressed in various tumor types G250: expressed in renal cell carcinoma GD2: ganglioside 2, a disialoganglioside expressed by neuroblastoma and melanoma HMFG 1 and 2: antigenic motifs recognized by the HMFG-1 and HMFG-2 monoclonal antibodies, and present at high levels in the serum of patients with breast and ovarian cancer MUC1: mucin 1, a membrane protein expressed by epithelial cells and that shows aberrant glycosylation in colorectal, pancreatic, breast and ovarian cancers TAG-72: tumor-associated glycoprotein-72, a mucin-like glycoprotein expressed in ovarian, pancreatic and colorectal cancer TN-C: tenascin-C, an extracellular matrix glycoprotein involved in cell adhesion and migration, and overexpressed in high-grade glioma PSMA: prostate-specific membrane antigen, highly expressed in all prostate cancers

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Table 2. Radionuclides used in radioimmunotherapy. Radionuclides Daughter isotope

Half-life

Maximum energy (keV)

Maximum range (µm)

b-particle emitters (LET 0.2 keV/ µm) Y

–

64.1 h

2284

11,300

I

–

193.0 h

606

2300

Lu

–

161.0 h

497

1800

Cu

–

61.9 h

575

2100

90

131

177 67

186

Re

–

90.6 h

1077

4800

188

Re

–

17.0 h

2120

10,400

Auger particle emitters (LET 4–26 keV/µm for very low [