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Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

Survey of Clinical Translation of Cancer NanomedicinesLessons Learned from Successes and Failures Published as part of the Accounts of Chemical Research special issue “Nanomedicine and Beyond”. Hongliang He,† Lisha Liu,† Emily E. Morin,† Min Liu,‡ and Anna Schwendeman*,†,§

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†

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109, United States ‡ Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 200032, PR China § Biointerfaces Institute, NCRC Building, 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States CONSPECTUS: In 1995, the year the first cancer nanomedicine, Doxil, was approved by the Food and Drug Administration (FDA), only 23 manuscripts appeared in a PubMed search for “nanoparticles for cancer” keywords. Now, over 25 000 manuscripts can be found using those same keywords, yet only 15 nanoparticle-based cancer nanomedicines are approved globally. Based on the clinicaltrials.gov database, a total of 75 cancer nanomedicines are under clinical investigation involving 190 clinical trials summarized here. In this Account, we focus on cancer nanomedicines that have been approved or reached clinical trials to understand this high attrition rate. We classify the various nanomedicines, summarize their clinical outcomes, and discuss possible reasons for product failures and discontinuation of product development efforts. Among ongoing and completed clinical trials, 91 (48 completed) are phase 1, 78 (59 completed) phase 2, and 21 (11 completed) phase 3. The success rate of phase 1 trials has been highroughly 94%. Of those phase 1 trials with identified outcomes, 45 showed positive safety and efficacy results, with only one negative result (low efficacy) and two terminated due to adverse reactions. In some cases, findings from these trials have not only shown improved pharmacokinetics, but also avid drug accumulation within tumor tissues among active-targeting nanoparticles, including BIND-014, CALAA-01, and SGT-94. However, the success rate drops to ∼48% among completed phase 2 trials with identified outcomes (31 positive, 15 negative, and 4 terminated for toxicity or poor efficacy). A majority of failures in phase 2 trials were due to poor efficacy (15 of 19), rather than toxicity (4 of 19). Unfortunately, the success rate for phase 3 trials slumps to a mere ∼14%, with failures stemming from lack of efficacy. Although the chance of success for cancer nanomedicines starting from the proof-of-concept idea in the laboratory to valuable marketed product may seem daunting, we should not be discouraged. Despite low success rates, funding from the government, foundations, and research organizations are still strongan estimated > $130 M spent by the National Institutes of Health (NIH) on R01s focused on nanomedicine in 2018 alone. In addition, the NIH created several special initiatives/programs, such as the National Cancer Institute (NCI) Alliance, to facilitate clinical translation of nanomedicines. Companies developing cancer nanomedicines raised diverse ranges of funds from venture capital, capital markets, and industry partnerships. In some cases, the development efforts resulted in regulatory approvals of cancer nanomedicines. In other cases, clinical failures and market pressure from improving standard of care products resulted in product terminations and business liquidation. Yet, recent approvals of nanomedicine products for orphan cancers and continuing development of nanoparticle based drugs for immuneoncology applications fuel continuing industrial and academic interest in cancer nanomedicines.

1. INTRODUCTION

Thus, the demand for novel and effective cancer medicine to curb high mortality is urgent. With the rapid advancement of nanotechnology into medicine, cancer nanomedicines have made dramatic progress over the past several decades. To increase the accumulation of

Cancer continues to be one of the most difficult global healthcare problems. In the Cancer Facts & Figures of 2018, the American Cancer Society reports that cancer is the second most common cause of death in the US, exceeded only by heart disease.1 About 1.7 million new cancer cases are expected to be diagnosed in 2018. About 609 640 Americans are expected to die of cancer in 2018, translating to about 1670 deaths per day. © XXXX American Chemical Society

Received: April 30, 2019

A

DOI: 10.1021/acs.accounts.9b00228 Acc. Chem. Res. XXXX, XXX, XXX−XXX

Article

Accounts of Chemical Research

Figure 1. Overview of cancer nanomedicines approved and in clinical development.

Figure 2. Timeline of approval for 15 marketed cancer nanomedicines worldwide

were the fundamental principles of first-generation cancer nanomedicines (like Doxil), which were simple lipid vesicles shielded with polyethylene glycol (PEG) to prevent immune response and prolong circulation time. Next-generation cancer nanomedicines have used tissue-specific ligand coatings to better target tumors (such as BIND-014),5 as well as stimulicontrolled payload release (like ThermoDox) to increase the drug tumor accumulation.6 The goal was simple: the right drug should be delivered to the right location of the right patient at the right time in the right concentration with limited systemic toxicity. Based on our best analysis, there are currently 75 cancer nanomedicines in clinical trials (summarized in Figure 1). However, the translation of nanotechnology platforms from universities, small and medium enterprises (SMEs), or large pharmaceutical companies into clinical development and

chemotherapeutic agents within the tumor, while sparing the distribution in normal tissues, researchers in both academia and industry have engineered various nanoparticles capable of delivering therapeutic and diagnostic agents selectively to tumors.2−4 Such nanoparticles include liposomes, polymeric or lipid nanoparticles, inorganic nanoparticles, polymer−drug conjugates, polymeric micelles, etc. Antibody−drug conjugates were not considered in the scope of this Account because it is an important therapeutic class distinct from the nanoparticle-based nanomedicines discussed here. The payloads include chemotherapeutic agents, therapeutic nucleic acids, and immunotherapeutic agents. The tumor targeting strategies involved can be categorized into (1) passive targeting based on the enhanced permeability and retention (EPR) effect, (2) active targeting directed by tumor specific moieties, and (3) stimuli-responsive tumor targeting. Particle size control and passive EPR targeting B


Article

Accounts of Chemical Research Table 1. Clinically Approved Cancer Nanomedicines for Indications and Clinical Outcome Update proprietary name/composition Doxil/Caelyx (PEGylated liposomal doxorubicin)

DaunoXome (liposomal daunorubicin) Myocet (liposomal doxorubicin) Lipusu (liposomal paclitaxel) Abraxane (albumin-bound paclitaxel)

Oncaspar (L-asparaginase conjugate) DepoCyt (liposomal cytarabine)

indication

clinical outcomes

progression-free survival (PFS, months): Caelyx (6.9) vs reference arm (7.8), p = 0.99 overall survival (OS, months): Caelyx (21) vs reference arm (22), p = 0.59 overall response rate (ORR,%): Caelyx (68) vs reference arm (77) ovarian cancer OS (months): Doxil (14.4) vs reference arm (13.7), p = 0.55 OS (days): Caelyx (756) vs reference arm (498) time to progression (TTP, days): Caelyx (202) vs reference arm (163) myeloma duration of response (months): Doxil (10.2) vs reference arm (7.0) ORR (%): Doxil (48) vs RA (43), p = 0.251 TTP (days): Doxil (282) vs RA (197), p < 0.0001. Kaposi’s sarcoma ORR (%): DaunoXome (25) vs reference arm (28) OS (days): DaunoXome (369) vs reference arm (342) breast cancer ORR (%): Myocet arm (46) vs reference arm (39), p = 0.42 TTP (months): Myocet arm (5.7) vs reference arm (4.4), p = 0.01 OS (months): Myocet arm (18.3) vs reference arm (16.0), p = 0.504 breast and non-small-cell lung cancer ORR (%): Lipusu (47) vs reference arm (46) disease control rate (%): Lipusu (73) vs reference arm (71) breast cancer ORR (%): Abraxane (26.5) vs reference arm (13.2), p = 0.006 TTP (weeks): Abraxane (20.9) vs reference arm (16.1), p = 0.011 PFS (weeks): Abraxane (20.6) vs reference arm (16.1), p = 0.01 OS (weeks): Abraxane (56.4) vs reference arm (46.7), p = 0.020 pancreatic adenocarcinoma ORR (%): Abraxane (99) vs reference arm (31), p < 0.0001 PFS (months): Abraxane (5.5) vs reference arm (3.7), p < 0.0001 OS (months): Abraxane (8.5) vs reference arm (6.7), p < 0.0001 non-small-cell lung cancer ORR (%): Abraxane (33) vs reference arm (25), p = 0.005 PFS (months): Abraxane (6.8) vs reference arm (6.5) OS (months): Abraxane (12.1) vs reference arm (11.2) leukemia the 3-year event-free survival was similar in the Oncaspar and reference arm breast cancer

solid tumors or leukemia

OS (days): DepoCyt (99.5) vs reference arm (63) ORR (%): DepoCyt (41) vs reference arm (6) lymphoma ORR (%): DepoCyt (33) vs reference arm (17) Genexol-PM (paclitaxel breast cancer ORR (%): Genexol-PM (31.9) vs reference arm (24.3), P = 0.016 micellar) OS (months): Genexol-PM (28.8) vs reference arm (23.8), p = 0.52 PFS (months): Genexol-PM (8.0) vs reference arm (6.7), p = 0.26 Mepact (liposomal osteogenic sarcoma the addition of Mepact significantly increased the 6-year overall survival and resulted in a mifamurtide) relative reduction in the risk of death by 28%, (p = 0.0313) Marqibo (liposomal leukemia complete remission (CR) rate (%): Marqibo (3) vinCRIStine sulfate) rate of CR with incomplete blood count recovery (CRi,%): Marqibo (7) In patients who achieved a CR or CRi, the median remission duration was 28 days and the median time to first event was 56 days. PICN (paclitaxel breast cancer ORR (%): PICN 260 mg/m2 (35) vs PICN 295 mg/m2 (49) vs reference arm (43) nanosuspension) PFS (weeks): PICN 260 mg/m2 (23) vs PICN 295 mg/m2 (35) vs reference arm (34) ONIVYDE (liposomal pancreatic adenocarcinoma OS (months): ONIVYDE (6.1) vs reference arm (4.2), p = 0.014 irinotecan) PFS (months): ONIVYDE (3.1) vs reference arm (1.5) ORR (%): ONIVYDE (9) vs reference arm (1) DHP107 (paclitaxel lipid gastric cancer PFS (months): DHP107 (3.0) vs reference arm (2.6) nanoparticle) ORR (%): DHP107 (17.8) vs reference arm (25.4) OS (months): DHP107 (9.7) vs reference arm (8.9) Vyxeos (liposomal leukemia OS (months): Vyxeos (9.6) vs reference arm (5.9), p = 0.005 daunorubicin and cytarabine) ORR (%): Vyxeos (58) vs reference arm (41), p = 0.036 Apealea (paclitaxel micellar) ovarian cancer, peritoneal cancer, and PFS (months): Apealea (10.3) vs reference arm (10.1), p = 0.0938 fallopian tube cancer OS (months): Apealea (25.7) vs reference arm (24.8), p = 0.6202

2. OVERVIEW OF CLINICAL OUTCOMES FOR APPROVED CANCER NANOMEDICINES From the first FDA approval of Doxil to the latest European Medicines Agency (EMA) approval of Apealea, there are at least 15 cancer nanomedicines on the market (NanoTherm approved by EMA as medical devices not included here). Their approval timelines are summarized in Figure 2, while clinical outcomes are detailed in Table 1.

commercial success is formidably difficult with a high attrition rate. The clinical outcomes for approved products and those in clinical trials are summarized below, together with the potential reasons for low translational success and lessons that could be learned from these clinical failures. C


liposomal Annamycin

PEGylated liposomal cisplatin PEGylated liposomal doxorubicin PEGylated liposomal docetaxel PEGylated Liposomal irinotecan PEGylated liposomal cisplatin PEGylated liposomal CKD-602 transferrin ligand-directed liposomal oxaliplatin

Liposomal Annamycin

LiPlaCis ATI-0918 ATI-1123 IHL-305 Lipoplatin S-CKD602 MBP-426

D

36

29 30 31 32 33 34 35

28

18 19 20 21 22 23 24 25 26 27

liposomal lurtotecan liposomal SN-38 liposomal paclitaxel

OSI-211 LE-SN38 LEP-ETU

4 5 6 7 8 9 10 11 12 13 14 15 16 17

thermally sensitive liposomal doxorubicin

liposomal small activating RNA of CEBPA liposomal protein kinase N3 siRNA liposomal shRNA against human stathmin 1

ThermoDox

MTL-CEBPA Atu027 pbi-shRNA STMN1 LP pbi-shRNA EWS/FLI1 LP SGT-53

liposomal EphA2 siRNA

liposomal miR-34

MRX34

EphA2-siRNADOPC

liposomal RB94 plasmid liposomal KSP/VEGF siRNAs

SGT-94 ALN-VSP02

liposomal p53 plasmid

liposomal shRNA against EWS/FLI1

HER2-targeted antibody−liposomal doxorubicin EphA2-targeting liposomal docetaxel prodrug anti-EGFR-targeting liposomal doxorubicin

MM-302 MM-310 C225-ILs-dox

liposomal vinorelbine

VLI

3

composition

liposomal bis-neodecanoate diaminocyclohexane platinum liposomal topotecan

Aroplatin TLI

proprietary name

1 2

no.

developer

developed by Mirna Therapeutics (now acquired by Synlogic) M.D. Anderson Cancer Center

Alnylam Pharmaceuticals

SynerGene Therapeutics

MiNA Therapeutics Silence Therapeutics Gradalis

Celsion

University Hospital, Basel, Switzerland

Merrimack Pharmaceuticals

Yakult Honsha Regulon Johnson & Johnson Mebiopharm

Oncology Venture Cytori Therapeutics

Moleculin Biotech

Astellas Pharma Insys Therapeutics

Agenus Spectrum Pharmaceuticals

Table 2. Summary of 91 Phase 1 Clinical Trials for Cancer Nanomedicines indication

advanced tumors

advanced tumors

solid tumors advanced tumors

advanced tumors CNS malignancies

advanced Ewing’s sarcoma

advanced or refractory tumors ovarian cancer solid tumors advanced solid tumors advanced tumors advanced tumor solid tumors gastric, gastroesophageal, or esophageal adenocarcinoma breast cancer solid tumors solid tumors gliomas liver tumors hepatocellular carcinoma breast cancer liver cancer solid tumors advanced cancer

leukemia

advanced solid tumors small-cell lung cancer, ovarian cancer, and other advanced tumors solid tumors, non-Hodgkin’s lymphoma or Hodgkin’s disease advanced solid tumors advanced tumors

NCT number

NCT01591356

NCT00470613 NCT03554707 NCT02354547 NCT01517464 NCT00882180 NCT01158079 NCT01829971

NCT02736565

NCT01304797 NCT03076372 NCT01702129 NCT03603379 NCT02181075 NCT02112656 NCT03749850 NCT02716012 NCT00938574 NCT01505153

NCT00003891 NCT00046540 NCT00080418 NCT00100139 NCT03315039 NCT03388749 NCT01861496 NCT01715168 NCT01041235 NCT00364143 not identified NCT00177281 NCT00355888 NCT00964080

NCT00364676

NCT00057395 NCT00765973

status

ongoing

completed ongoing ongoing completed completed completed terminated

ongoing

completed terminated completed ongoing completed completed ongoing ongoing completed completed

completed completed completed completed ongoing ongoing ongoing completed completed completed completed completed completed ongoing

completed

unknown ongoing

positive positive positive toxicity

positive

positive positive

positive positive

positive toxicity positive

positive positive positive positive positive positive

positive positive positive positive

positive

outcome

Accounts of Chemical Research Article


DPX-Survivac

DPX-E7

DPX-0907

Lipovaxin-MM

dHER2+AS15

40 41 42 43

44

45

46 47 48 49

composition

E

DCR-MYC

64

67 68 69 70 71

AuroShell EZN-2208

CYT-6091 NBTXR3

gold-silica nanoshells polyethylene glycol-SN38 conjugate

TNF-bound colloidal gold hafnium-oxide nanoparticle

polyethyleneimine complexed with eIF5AK50R plasmid DNA lipid nanoparticle containing PLK1 siRNA transferrin receptor-targeted nanoparticle containing anti-RRM2 siRNA lipid nanoparticle containing MYC siRNA

SNS01-T TKM-PLK1 CALAA-01

59 60 61 62 63

65 66

prostate-specific membrane antigen-targeted nanoparticle containing docetaxel PEG-PEI-cholesterol nanoparticle containing IL-12 DNA plasmid

BIND-014

GEN-1

albumin-bound rapamycin nanoparticle

paclitaxel microsphere prostate-specific membrane antigen-targeted nanoparticlecontaining aurora B kinase inhibitor

liposomal 7 tumor-specific HLA-A2-restricted peptides, a universal T Helper peptide and a polynucleotide adjuvant dendritic cell receptor ligand-bearing liposome-encapsulated melanoma antigens truncated HER2 protein in combined with the immunological liposomal AS15 adjuvant

liposomal E7 peptide of the HPV-16 protein

liposomal DNA interference oligonucleotides PNT100 liposomal DNA complex containing immunostimulatory CpG and non-CpG motifs liposomal six human papillomavirus 16 (HPV-16) E6 and E7 peptides liposomal survivin-based synthetic peptide antigens and an adjuvant

ABI-009

50 51 52 53 54 55 56 57 58

PDS0101

39

AI-850 AZD2811

PNT2258 JVRS-100

proprietary name

37 38

no.

Table 2. continued developer

Nanospectra Biosciences Enzon Pharmaceuticals

CytImmune Nanobiotix

Dicerna Pharmaceuticals

Sevion Therapeutics Arbutus Biopharma Calando Pharmaceuticals

Celsion

BIND therapeutic (acquired by Pifzer)

Aadi Bioscience

Acusphere BIND therapeutic (acquired by Pifzer); Now developed by AstraZeneca

GlaxoSmithKline

Lipotek Pty

ImmunoVaccine

PDS Biotechnology

Sierra Oncology Colby Pharmaceutical

indication

advanced tumors head and neck cancer or non-smallcell lung cancer prostate adenocarcinoma liver cancer head and neck cancer advanced tumors

solid tumors, myeloma, or lymphoma

myeloma or lymphoma liver cancer solid tumors

ovarian cancer

solid tumor myeloid leukemia/myelodysplastic syndrome advanced tumors solid tumors nonadipocytic soft tissue sarcomas colorectall cancer nonhematologic malignancies bladder cancer advanced sarcoma myeloma advanced tumors

breast cancer

malignant melanoma

ovarian cancer HPV-16-related oropharyngeal, cervical, and anal cancer ovarian, breast and prostate cancer

ovarian, fallopian, or peritoneal cancer

cervical intraepithelial neoplasia

advanced tumors leukemia

NCT number

NCT02805894 NCT02721056 NCT00848042 NCT00520390 NCT01251926

NCT00356980 NCT03589339

NCT02110563


NCT02579226 NCT02975882 NCT03660930 NCT03439462 NCT00635284 NCT02009332 NCT03190174 NCT03657420 NCT01300533

NCT00140738 NCT00058526 not identified NCT03217838

NCT01052142

NCT01095848

NCT03332576 NCT01416038 NCT02785250 NCT02865135

NCT02065973

NCT01191775 NCT00860522

status

ongoing ongoing completed completed completed

completed ongoing

terminated

ongoing ongoing completed completed terminated

ongoing ongoing ongoing ongoing completed ongoing ongoing ongoing completed

completed completed completed ongoing

completed

completed

ongoing completed ongoing ongoing

completed

completed ongoing

outcome

positive positive positive

sponsor decision positive

positive unknown unknown

positive

positive


negative

positive

positive

positive

positive



F

91

83 84 85 86 87 88 89 90

72 73 74 75 76 77 78 79 80 81 82

no.

bacterially based nanocell containing mitoxantrone

EGFR EDVmitoxantrone EGFR EDVDox

bacterially based nanocell containing doxorubicin

epirubicin micellar oxaliplatin micellar doxorubicin micellar SN-38 micellar

cyclodextrin-PEG copolymer conjugated with docetaxel diaminocyclohexane platinum polymer conjugate doxorubicin micellar docetaxel micellar cisplatin micellar

CRLX301 ProLindac SP1049C CPC634 NC-6004

NC-6300 NC-4016 NK911 NK012

camptothecin polymer conjugate irinotecan-PEG conjugate camptothecin poly l-glutamate conjugate camptothecin−cyclodextrin conjugate

composition

XMT-1001 NKTR-102 CT-2106 CRLX101

proprietary name

Table 2. continued

EnGeneIC

Nippon Kayaku

Abeona Therapeutics Supratek Pharma Cristal Therapeutics NanoCarrier

Mersana Therapeutics Nektar Therapeutics CTI BioPharma NewLink Genetics

developer

indication

glioblastoma

solid tumors and colorectal cancer solid or CNS tumors

solid tumors or soft tissue sarcoma solid tumors or lymphoma solid tumors

solid tumor advanced cancer solid tumors solid tumors or non-small-cell lung, biliary, and bladder cancer head and neck cancer

solid tumors solid tumors solid tumors advanced tumors small-cell lung cancer solid tumors

NCT number

NCT02766699

NCT02817113 NCT03109158 NCT03168061 NCT03168035 not identified NCT00542958 NCT01238939 NCT02687386

NCT01295697 NCT00455052 NCT01991678 NCT00059917 NCT02769962 NCT02648711 NCT02380677 not identified not identified NCT02442531 NCT02240238

status

ongoing

unknown ongoing ongoing completed completed completed completed ongoing

completed completed completed completed ongoing ongoing ongoing completed completed completed ongoing

outcome

unknown positive positive positive


positive positive positive positive



Article

Accounts of Chemical Research Table 3. Summary of 78 Phase 2 Clinical Trials for Cancer Nanomedicines no.

proprietary name

composition

developer

92

CPX-1

liposomal irinotecan and floxuridine

93 94

Aroplatin

liposomal bis-neodecanoate diaminocyclohexane platinum

95 96 97 98 99 100 101

OSI-211

liposomal lurtotecan

Astellas Pharma

LE-SN38 LEP-ETU Liposomal Annamycin Atragen SPI-077

liposomal SN-38 liposomal paclitaxel liposomal annamycin

Insys Therapeutics

liposomal tretinoin liposomal cisplatin

Agenus Johnson & Johnson

EndoTAG-1

liposomal paclitaxel

SynCore Biotechnology

2B3-101

BBB-Therapeutics BV Regulon Celsion

Silence Therapeutics SynerGene Therapeutics

102 103 104 105 106 107 108 109 110

Jazz Pharmaceuticals Agenus

Moleculin Biotech

111 112 113

Lipoplatin ThermoDox

glutathione PEGylated liposomal doxorubicin PEGylated liposomal cisplatin thermally sensitive liposomal doxorubicin

114

Atu027

liposomal protein kinase N3 siRNA

115 116 117 118 119 120 121 122 123 124 125 126 127 128

SGT-53

liposomal p53 plasmid

PNT2258

liposomal DNA interference oligonucleotides PNT100

Sierra Oncology

Allovectin-7 Tecemotide

liposomal VCL-1005 plasmid liposomal MUC1 antigen

Vical Merck KGaA

129

Doxorubicin Transdrug ABI-009

130 131

134 135 136 137

status

NCT00361842

completed

positive

colorectal cancer malignant pleural mesothelioma head and neck cancer ovarian cancer small-cell lung cancer ovarian cancer colorectal cancer breast cancer leukemia

NCT00043199 NCT00004033

completed completed

positive negative

NCT00022594 NCT00010179 NCT00046787 NCT00046800 NCT00311610 NCT01190982 NCT00271063

completed completed completed completed completed completed completed

negative positive unknown unknown negative unknown positive

NCT00003656 not identified NCT00004083 not identified NCT00377936 NCT00448305 NCT01537536 NCT00542048 NCT01386580

completed completed completed completed completed completed completed completed completed

unknown negative negative negative positive positive positive positive positive

non-small-cell lung cancer breast cancer

not identified NCT00826085 NCT00346229

completed completed terminated

pancreatic cancer

NCT01808638

completed

positive positive finding issue positive

pancreatic cancer glioblastoma lymphoma

ongoing ongoing completed terminated completed ongoing completed completed completed completed ongoing ongoing ongoing completed

kidney cancer non-small-cell lung cancer ovarian cancer head and neck cancer pancreas cancer breast cancer advanced cancers solid tumors and brain cancer

outcome

DPX-Survivac

liposomal survivin-based synthetic peptide antigens and an adjuvant

ImmunoVaccine

dHER2+AS15

truncated HER2 protein in combined with the immunological liposomal AS15 Adjuvant nanoparticles containing doxorubicin

GlaxoSmithKline

breast cancer

Onxeo

hepatocellular carcinoma

not identified

completed

albumin-bound rapamycin nanoparticle

Aadi Bioscience

glioblastoma perivascular epithelioid cell tumor lung or gastroenteropancreatic cancer advanced cervical or head and neck cancer prostate cancer non-small-cell lung cancer

NCT03463265 NCT02494570

ongoing ongoing

NCT03670030

ongoing

NCT02479178

terminated

negative

NCT01812746 NCT02283320 NCT01792479 NCT01612546

completed completed completed completed

positive positive positive negative

NCT02187302 NCT01380769 NCT02389985

completed completed ongoing

negative negative

NCT01262235

completed

positive

BIND-014

CRLX101

prostate-specific membrane antigentargeted docetaxel-containing nanoparticle (ACCURINS)

BIND therapeutic (acquired by Pifzer)

nanoparticles consisted of camptothecin− cyclodextrin conjugate

NewLink Genetics

138 139 140 141

indication

NCT02340117 NCT02340156 NCT01733238 NCT02226965 NCT00003646 NCT00828009 NCT01462513 NCT01507103 NCT01496131 NCT01094548 NCT03029403 NCT02323230 NCT03349450 NCT00952692

132

133

NCT number

colorectal cancer

TKM-PLK1

lipid nanoparticle containing PLK1 siRNA

Arbutus Biopharma G

melanoma non-small-cell lung cancer colorectal cancer rectal cancer prostate cancer myeloma ovarian cancer lymphoma

stomach, gastroesophageal, or esophageal cancer kidney cancer non-small-cell lung cancer ovarian, fallopian tube, or primary peritoneal cancer neuroendocrine tumors and adrenocortical carcinoma

positive negative positive unknown unknown unknown unknown

positive

positive


Article

Accounts of Chemical Research Table 3. continued no.

proprietary name

composition

developer

indication

142 143

DCR-MYC

lipid nanoparticle containing MYC siRNA

144

NanoTherm

145 146 147

EZN-2208

superparamagnetic iron oxide nanoparticles SN38 PEG conjugate

ProLindac

platinum polymer conjugate

148 149 150 151 152 153 154 155

NKTR-102

irinotecan PEG conjugate

Taxoprexin

paclitaxel DHA conjugate

Luitpold Pharmaceuticals

156 157 158 159 160 161 162 163 164 165 166 167

CT-2103

paclitaxel poliglumex conjugate

CTI BioPharma

CT-2106

camptothecin polymer conjugate

NK012

SN-38 micellar

Nippon Kayaku

SP1049C

doxorubicin micellar

Supratek Pharma

168

CPC634

docetaxel micellar

169

NC-6004

cisplatin micellar

Cristal Therapeutics NanoCarrier

Dicerna Pharmaceuticals MagForce AG Enzon Pharmaceuticals Abeona Therapeutics Nektar Therapeutics

NCT number

status

hepatocellular carcinoma hepatocellular carcinoma

NCT02191878 NCT02314052

completed terminated

positive negative

glioblastoma

not identified

completed

positive

colorectal cancer breast cancer solid tumor

NCT00931840 NCT01036113 not identified

completed completed unknown

negative positive

breast cancer glioma ovarian cancer colorectal cancer non-small-cell lung cancer lung and breast cancer eye melanoma liver cancer

NCT00802945 NCT01663012 NCT00806156 NCT00856375 NCT01773109 NCT02312622 NCT00244816 NCT00422877

completed completed completed completed completed ongoing completed terminated

positive positive positive positive negative

non-small-cell lung cancer breast cancer prostate cancer esophageal cancer non-small-cell lung cancer glioblastoma

NCT00487669 NCT00265733 NCT00446836 NCT00522795 NCT00352690 NCT01402063 NCT00763750 NCT00291785 NCT00291837 NCT00951054 NCT00951613 not identified

completed completed completed completed terminated completed completed completed completed completed completed completed

NCT03742713

ongoing

NCT00910741

completed

colorectal cancer ovarian cancer breast cancer small-cell lung cancer advanced esophagus or gastresophageal junction adenocarcinoma ovarian cancer pancreatic cancer

outcome

negative sponsor decision unknown negative unknown positive toxicity negative negative unknown unknown unknown positive positive

positive

government’s healthcare system and avoid undue financial burden on patients with cancer.

Continuous improvements in cancer therapy have been made over the past three decades with the advent of cancer nanomedicines, including prolonged overall survival, increased overall response rate and reduced systemic toxicity.7 However, cancer nanomedicines still face broad controversy due to marginal prolongations in clinic (Table 1). In addition, cancer nanomedicines pose a heavy financial burden to both patients and health insurers when compared to standard treatment or “free” drug alone. A survey found that oncology patients and their insurers paid an average of $54 100 for an additional year of life in 1995, but the price had jumped to $207 000 by 2013.8 In one example, Anthem, the second largest U.S. health insurer, regarded Abraxane (∼$10 000 per dose vs paclitaxel at ∼$200 per dose) as “overused relative to their value,” given the product sales report from Celgene, showing Abraxane’s net product sales of $288 M for the third quarter of 2018, a 15% increase from the same period in 2017. Hence, there is still a long way to go in maximizing the value of cancer nanomedicines to be curable and affordable for all of society. Discussions to reduce healthcare costs without compromising treatment efficacy and patient safety should involve cooperation among oncologists, pharmaceutical companies, pharmacy benefit management, health insurers, and regulatory agencies, as well as the federal government. Only then can we come up with acceptable solutions that secure financial profit to pharmaceutical companies but safeguard the economic infrastructure of the

3. CLINICAL TRIALS SUMMARY FOR CANCER NANOMEDICINES IN DEVELOPMENT In this section, we searched for cancer nanomedicines still in clinical trials based on clinicaltrials.gov, developers’ reports and other available Internet resources. In total, we summarize 190 clinical trials, including phase 1 (91 trials), 2 (78 trials), and 3 (21 trials). Phase 1 studies are summarized in Table 2. Out of 91 total trials, 48 have been completed, 38 are ongoing, 4 have been terminated, and 1 has unknown status. Overall, 45 of 48 completed phase 1 studies reported positive outcomes, reaching the sponsor’s expectation, including acceptable safety profile and, in some instances, improved pharmacokinetics over free drug and signs of antitumor efficacy. Only one trial reported a negative outcome of low efficacy (Lipovaxin-MM, NCT01052142), two were terminated due to adverse reactions (MM-310, NCT03076372 and MRX34, NCT01829971), and the results of two studies were not reported. Considering that 45 out of 48 completed studies had positive results, the success rate for phase 1 is ∼94%. Of those 78 phase 2 trials (Table 3), 59 have been completed, 12 are currently ongoing, 6 were terminated prematurely, and 1 trial has unknown status. In the completed 59 phase 2 trials, 31 presented positive outcomes, meeting set safety and efficacy H


Article

Accounts of Chemical Research Table 4. Summary of Phase 3 Clinical Trials for Cancer Nanomedicine Products no.

proprietary name

composition

developer

170

Lipoplatin

PEGylated liposomal cisplatin

Regulon

171 172

EndoTAG-1

liposomal paclitaxel

SynCore Biotechnology

173

MM-302

174

ThermoDox

HER2-targeted liposomal doxorubicin hydrochloride thermally sensitive liposomal doxorubicin

Merrimack Pharmaceuticals Celsion

175 176

Allovectin-7 Tecemotide

liposomal VCL-1005 plasmid liposomal MUC1 antigen

Vical Merck KGaA

177 178

MAGEA3+AS15

human melanoma-associated antigen A3 protein in combination with the immunological liposomal AS15 adjuvant

GlaxoSmithKline

179

Doxorubicin Transdrug NBTXR3

nanoparticles containing doxorubicin

Onxeo

hafnium-oxide nanoparticle

Nanobiotix

181 182

Taxoprexin

paclitaxel DHA conjugate

Luitpold Pharmaceuticals

183 184 185

NKTR-102

irinotecan PEG conjugate

Nektar Therapeutics

CT-2103

paclitaxel polymer conjugate

CTI BioPharma

180

186 187 188 189 190

NC-6004 NK105

cisplatin micellar paclitaxel micellar

NanoCarrier

indication

NCT number

status

outcome

non-small-cell lung cancer breast cancer pancreatic adenocarcinoma breast cancer

not identified

completed

NCT03002103 NCT03126435

ongoing ongoing

NCT02213744

terminated

negative

hepatocellular carcinoma melanoma non-small-cell lung cancer melanoma non-small-cell lung cancer hepatocellular carcinoma sarcoma

NCT00617981

completed

positive

NCT00395070 NCT00409188

completed completed

negative negative

NCT00796445 NCT00480025

terminated terminated

negative negative

NCT01655693

ongoing

NCT02379845

ongoing

not identified NCT00243867

completed completed

NCT02915744 NCT01492101 NCT00108745

ongoing completed ongoing


completed completed completed unknown completed

melanoma non-small-cell lung cancer breast cancer ovarian, peritoneal, or fallopian tube cancer non-small-cell lung cancer pancreatic cancer breast cancer

positive

positive (interim data) negative unknown

negative

negative negative negative negative

trials (both terminated and completed), 15 trials observed lower efficacy (71.4%) and 4 trials reported adverse reactions (26.7%). All of the 11 failed phase 3 trials (both terminated and completed) were due to lower efficacy.

end-points, while 15 trials missed their primary end points (3 with toxicity concerns and 12 with lower efficacy compared to the reference arm). Thirteen of the completed trials do not report clinical outcomes. Among those six terminated trials, three were associated with lower efficacy (PNT2258, NCT02226965; BIND-014, NCT02479178, and DCR-MYC, NCT02314052), one with associated toxicity (CT-2103, NCT00352690), one with funding issues (ThermoDox, NCT00346229), as well as one for unknown reasons (Taxoprexin, NCT00422877). Together, the success rate of phase 2 trials drops to ∼48%, considering that 31 positive trials came out of 59 completed trials and 6 terminated trials. Among those 21 phase 3 trials (Table 4), six are currently ongoing and 11 have been completed. In addition, one has unknown status, and three trials were terminated due to low efficacy (MM-302, NCT02213744; MAGE-A3+AS15, NCT00796445, and NCT00480025). Among the 11 completed phase 3 trials, eight had negative results, two reported positive outcomes, and the results of another were not announced. Thus, the success rate of phase 3 is a mere ∼14% with only two positive outcomes out of 11 completed and 3 terminated trials. The success rates of phase 1, 2, and 3 trials significantly plunge from 94% to 48% to 14% (Figure 3). The high success rate of phase 1 trials suggests good material safety and, in some cases, improved pharmacokinetic profile relative to freely delivered drug. However, most phase 1 trials are purely designed to determine the maximum tolerable dose, a task successfully accomplished for most nanomedicines. Of the 21 failed phase 2

4. WHAT STOPS CANCER NANOMEDICINES DURING THE JOURNEY TO THE SUCCESS? In this section, while complete exploration of unknown explanations to the science behind those failed cancer nanomedicines is beyond our capability in this Account, we will examine many excellent existing reviews using different perspectives to declare some scientific explanations to the failures in the clinical translation of cancer nanomedicines.9−14 Here, we briefly summarized those well-acknowledged views behind those failures and sorted them using our own unique perspective into different viewpoints, including science, clinic, and market (schematically shown in Figure 4). 4.1. Science

4.1.1. Insufficient Understanding of Nanoparticle Interactions with Biological Components. When a nanoparticle comes in contact with blood, its surface is rapidly covered by a “corona” of serum proteins that influences nanoparticle physical stability, metabolism, clearance, and immune response.9,15 Size, shape, and surface charge, important physicochemical properties of nanoparticles, have critical influences on the interaction between nanoparticle and biological systems.15 Enhanced efforts are underway to develop I


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Figure 3. Statistical analysis of cancer nanomedicines still in clinical trials

reliable technologies to investigate the behavior of nanoparticles in a biological setting. These include the use of simulated in vivoJ


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Figure 4. Stop signs on the translational bridge for cancer nanomedicines

like blood medium, flow chambers for testing nanoparticle stability, and 3D microfluidic model culture systems to mimic the specific tumor microenvironment.16 4.1.2. Technical Challenges in Production. Sustainable production of clinical grade nanoparticles with high quality to meet Good Manufacturing Practice standards is another big hurdle for developing nanomedicines. For example, in 2012, the FDA allowed Sun Pharma Global FZE to temporarily import a supply of doxorubicin hydrochloride liposome injection (Lipodox) to alleviate the shortage of Doxil because of manufacturing constraints.17 In 2017, Pacira Pharmaceuticals discontinued all future production of DepoCyt due to unspecified technical problems in its manufacturing process.18 4.1.3. Clinical Safety Issues. Despite formal toxicology evaluation for all products entering clinical trial, toxicity related clinical failures still occur. For instance, in 2016 Mirna Therapeutics halted Phase 1 trial for MRX34 after one-fifth of patients experienced severe immune-related adverse events.19 In 2019, Merrimack terminated the development of MM-310 because of cumulative peripheral neuropathy observed in phase 1 trials.20 To eliminate potential toxicity-related clinical failure, researchers must not only understand the chemistry of nanoparticle formulation but also perform a thorough characterization of the nanoparticles, including physicochemical characterization, assessment of batch-to-batch consistency, and stability, sterility, and endotoxin quantification, blood contact properties, and in vivo cytotoxicity and immunotoxicology.21 4.1.4. The Controversial EPR. The major mechanism underlying the design of cancer nanomedicines is known as the enhanced EPR effect, and it is considered the “golden principle” in the passive tumor targeting drug delivery field.22 However, after thousands of research publications spanning several decades, the recent literature is increasingly highlighted by controversial statements: “EPR effect fails in the clinic” or “the

EPR effect works in rodents but not in humans”.23,24 Notably, EPR is reported to vary substantially between both patients and tumor types and even within the same patient or tumor type over time. 4.1.5. Poor Pharmacokinetics. Upon administration, a majority of injected nanomaterials are removed by the mononuclear phagocyte system (MPS) within minutes or hours, hindering efficacious, site-specific delivery to tumors and contributing to the nonspecific distribution of nanomaterials to healthy organs.15,25 Grafting of PEG to the nanoparticle surface can prevent binding of plasma proteins, thereby reducing MPS clearance and resulting in increased circulation time. Despite these achievements, a number of challenges have been reported after repeated injection of PEGylated material, including toxicity, immunogenicity, and inadequate cellular internalization. Several alternative strategies have been explored, including the modification of nanomaterials with “don’t eatme” proteins/peptides,26 as well as other biologically inspired strategies using cells27 or cell membranes to camouflage nanoparticles.28,29 4.1.6. Insufficient Accumulation in the Tumor. A recent meta-analysis of 117 cancer nanoparticle papers from the past 10 years found that only 0.7% (median) of the administered nanoparticle is delivered to a solid tumor, presenting a great challenge for cancer nanomedicine.10 Although data manipulation took place unblinded, superior tumor accumulations with cancer nanomedicines over the control arm is indeed observed in some recent clinical trials like, BIND-014,30 CALAA-0131 and SGT-94.32 In addition, the ability to precisely control drug release from nanoparticles via an external stimulus presents a promising approach to the problem. ThermoDox, developed by Celsion, significantly improved the overall survival by more than 25 months in patients with hepatocellular carcinoma when K


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Accounts of Chemical Research administered with optimized radiofrequency ablation in phase 3 trials.33 4.1.7. Limited Reliability and Validity of Cancer Animal Models. The lack of animal models able to recapitulate all aspects of human malignancy, including mutation, proliferation, and metastasis, has been a well-recognized reason for the discrepancy between the therapeutic efficacies observed in preclinical studies and the lack of positive clinical outcomes.9 For example, many preclinical studies are conducted on immune-deficient animals, making it difficult to predict potential adverse effectsparticularly immune suppression or activation in patients with intact immune systems. In addition, large differences in relative size have been observed between tumors implanted in animal models and those that develop naturally in patients.

4.2.4. Positive Clinical Data Does Not Guarantee Regulatory Approval. Many new applications fail to gain approval even with positive clinical results due to regulatory agency concerns, including insufficient justification on clinical comparator selection, inappropriate end point design, and inadequate methodology of clinical data analysis. For example, Opaxio’s European approval was denied despite a 42 day increment in overall survival for Opaxio versus comparator. Opaxio developer later decided to withdraw the application after concerns were raised by European officials over clinical trials regimen in 2009.37 Hence, it is necessary for pharmaceutical companies to seek advice from regulators prior and throughout the entire drug development process to identify potential concerns that may lead to non- or delayed approval.

4.2. Potential Reasons for Clinical Failures

According to the latest projection by the Tufts Center for Study of Drug Development (2014), the cost to develop a new drug is $2.558 billion, and this number has caused quite a storm. Many critics claim that these estimates are to justify high prices, are long on propaganda and short of details.38 Other estimates from the Office of Health Economics in 2012 came in at $1.506B. In addition, there is considerable variation based on the pharmaceutical maker, type of drug, and target indication. For example, their analysis found that the average cost of drug development was $521 M for one, while $2.1B for another.39 The general cost to develop a nanoparticle-based cancer nanomedicine has yet to be reported. 4.3.1. Failure of Clinical Trials Always Leads to Shrinking of Funding. Unlike the typical high-tech startup capable of launching a new product within months, a Biopharma startup often requires years of intensive funding to move their product from discovery through clinical trials toward regulatory approval. The cost of a failed clinical trial ranges from tens to hundreds of millions, depending on the trial size and stage of development.40 Those clinical trials missing primary end points always lead to stock selloffs, layoffs, inability to raise additional capital, and in many cases, company closure and fire sale of assets. 4.3.2. Is the Benefit Worth the Price? Once a product is approved, Pharma companies set exuberant prices for the medicines to recoup the cost of development within the remaining patent life span. The cost to patients is nearly 100 times higher for cancer nanomedicines (thousands of dollars per cycle) relative to generic chemotherapy drugs, while the benefit may be a mere months’ life prolongation.41 4.3.3. Growing Competition from New Therapeutic Agents. The standard of care for cancer patients is constantly changing. Recent approval of immune-check point antibodies, such as Opdivo and Keytruda, has revolutionized the treatment of several types of cancer, offering significant improvement in overall survival in patients responding to the therapy.42 In addition, several kinase inhibitors and other small molecule agents have been approved, making these easy-to-administer oral products significant competitors to cancer nanomedicines.43

4.3. Market

In addition to the design failures or drawbacks of nanomedicines in itself, there are also several other factors in clinical study design that could contribute to clinical trial failures. 4.2.1. The Loaded Molecule Does Not Work for the Selected Indication. Despite succeeding in three other phase 2 trials, BIND-014 failed in head and neck cancer (NCT02479178). When asked by the media on what went wrong about the failed trial of BIND-014, former BIND Therapeutic CEO Andrew Hirsch’s said, “the choice of payload is really important in terms of how it performs, and what the pharmaceutical properties of that payload are. I think for BIND014, I’m not convinced it was the right payload choice given what we now know about the treatment.”34 4.2.2. The Right Patient Selection Is Critical to Successful Clinical Trials. Selecting patients with a heterogeneous population, more advanced tumor development, or multiple complications can all contribute to poor clinical outcomes. Development of innovative approaches to timely monitor the distribution and transport of nanoparticles in vivo will provide a valuable reference for all pharmaceutical practitioners. Quantification of the EPR effect by imaging nanoparticle deposition in patient tumors would allow doctors to predict which tumors have greater susceptibility to the EPR effect and identify patients that are well suited for treatment with therapeutic nanoparticles. Merrimack has already applied this technique in clinical trials, showing positive outcomes (NCT01304797). 4.2.3. Finding the Right Combination Regimen to Maximize Clinical Efficacy. The future of nanomedicine development will likely take advantage of combined applications in the form of both multidrug nanomaterials and multimodal treatments. However, it may not be as trivial as delivering two agents within one nanoparticle. An emerging paradigm is that efficacy is governed by presenting two active agents in the right sequence or appropriate stoichiometric ratio. Temporal sequencing of active agents in combination therapy can be achieved using distinct linker chemistries or a layer-by-layer approach during nanoparticle fabrication.35 Appropriate stoichiometric ratios can be best embodied by the recent FDA approval of VYXEOS. For multimodal treatments, Cytimmune’s TNF-α labeled gold nanoparticle (CYT-6091, NCT00356980) was shown to successfully deliver TNF-α into tumors, disrupting their blood vessels to enhance follow-on chemotherapy in combination with gold nanoparticle-induced thermal tumor ablation.36

5. CAPITAL MARKETS AND GOVERNMENT FINANCING FOR CANCER NANOMEDICINE DEVELOPMENT The global nanomedicine market is anticipated to reach $350.8B by 2025, according to a new report by Grand View Research.44 The sales of top approved nanomedicine products brought in L


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Figure 5. Total funding for 21 cancer nanomedicine-based startups and SMEs

outcomes54 and MM-310 in 2019 due to toxicity.20 They currently have no nanoparticle-based products in development. In contrast, there are also capital efficient companies that developed cancer nanomedicine for orphan indications. One example, Celator Pharmaceuticals, raised ∼$170 M from VC, capital markets, and a grant from the Leukemia & Lymphoma Society for the development of products based on their proprietary CombiPlex technology platform. This led to eventual approval of Vyxeos to treat leukemia based on a 309 patient phase 3 trial.55 Similarly, we estimate that Oasmia Pharmaceutical raised ∼$248.4 M for the development of Apealea, which was approved by EMA in 2018 for ovarian cancer.56 It is too early to judge the full commercial success of these two products, but Vyxeos brought in $75 M in revenue in 2018, its first year after launch. With a significant interest in novel nanomedicine discovery from academia, NIH has stepped-up funding of both discovery efforts (through R01s) and development efforts (like Small Business Innovation Research). In 2004 the NCI launched the NCI Alliance for Nanotechnology in Cancer to develop and translate cancer-related nanotechnology research into clinical practice. The initiative encompasses 4 major program components: Centers of Cancer Nanotechnology Excellence (CCNEs), Nanotechnology Characterization Laboratory (NCL), Innovative Research in Cancer Nanotechnology, and Cancer Nanotechnology Training Centers. In May of 2019, the NCI announced it will stop funding the CCNEs in 2020. CCNEs received roughly $400 M over 15 years since its establishment in 2005, representing 10−20% of NCI’s funding for nanotechnology research. According to Dr. Grodzinski, the head of NCI’s Nanodelivery Systems and Devices Branch, “This [closure] doesn’t mean NCI’s interest in nanotechnology is decreasing. NCI will continue to support nanotechnology through R01s and other grant mechanisms.”57

$950 M (Abraxane), $275 M (Depocyte), and $252 M (Doxil/ Caelyx) in 2018. It is difficult and near impossible to accurately evaluate historic investments from venture capital (VC), capital markets and large pharmaceutical corporations in the development of cancer nanomedicines. Even the currently approved cancer nanomedicines have changed hands and faced threats of termination multiple times on the road to market approval. Doxil was developed by Sequus Pharmaceuticals, founded in 1981 (formerly Liposome Technology), and received approval in 1995.45 Sequus Pharmaceuticals was then acquired in 1998 by ALZA Pharmaceutical for $580M,46 which subsequently merged with Johnson & Johnson in 2001 in a $12.3B deal.47 In Figure 5, we summarized, to the best of our abilities, financing information for some of the companies with cancer nanomedicines in development. We retrieved the data from Crunchbase, Owler, historic press releases and media coverage to get financial information. All of them use nanotechnology for delivery of their products and currently have or have had in the past products in development for cancer treatment. Two companies focusing primarily on targeted delivery of chemotherapeutics are noted here. BIND Therapeutics, developing Accurins platform, was founded in 2007. It raised $70.5 M from VC, $102.2 M from capital markets, and $705 M in large Pharma partnerships.48 Yet, premature termination of the partnership with Amgen (due to unsatisfactory results)49 and a failed phase 2 study (NCT02479178) led to stock sell-off,50 plunged stock, and eventual acquisition by Pfizer for $40M.51 The second example, Merrimack Pharmaceutical, was founded in 2000 with a focus on liposomal chemotherapeutic delivery. We estimate that it raised $223 M from VC, $165 M from capital markets, and $1.643B from partnerships and out-licensing efforts.52 ONIVYDE and generic DOXIL, developed by Merrimack, were outlicensed by Ipsen for $1.025B, with ONIVYDE bringing in $122 M in sales for 2018.53 Merrimack discontinued development of antibody-directed liposomes MM-302 in 2016 due to negative M


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Figure 6. (a) This chart shows the total active R01 grants funded by NIH (dating to Dec. 2018) identified via searching terms “nanoparticles”, “nanocarriers”, or “nanomedicine” as keywords included in the funded project title or abstract using NIH RePORTER. (b) This graph shows the annual NIH R01s funding on nanomedicine in the past decade, measured by searching “nanoparticles”, “nanocarriers”, or “nanomedicine” as keywords included in the funded project title or abstract using NIH RePORTER. (c) The institute-specific programs funded by NIH.

to adapt to the microenvironmental change within the tumor, and immunologically engineered nanomaterials. With the recent clinical successes of immune checkpoint inhibitors and CAR Tcell therapy, using nanoparticles to effectively present immunestimulatory agents to the human immune system is key to generating a pivotal, sustained response against cancers previously unresponsive to conventional immunotherapies.59 For instance, a novel nonemulsion depot-forming vaccine platform, DepoVax (DPX), was developed by IMV to significantly enhance immunogenicity of peptide-based cancer vaccines. The lead candidate, DPX-Survivac, is currently undergoing phase 2 trials in multiple cancers either as monotherapy or in combination with Keytruda. We believe that the application of nanotechnology to cancer immunotherapy will lead to promising clinical outcomes based on their outstanding performance in preclinical studies. In conclusion, the lessons that we learned from the clinical translation of cancer nanomedicinies will give us a much deeper understanding of the fundamental interactions of nanoparticles and biological systems and the challenges and opportunities presented by the application of nanotechnology in cancer treatment. With 15 approved cancer nanomedicines and three other reporting positive phase 3 results, including Lipoplatin (Regulon), ThermoDox (Celsion), and interim report from NBTXR3 (Nanobiotix), it is clear that cancer nanomedicines

We searched the NIH RePORTER database using terms “nanoparticles”, “nanocarriers”, or “nanomedicine” and found 368 R01s focused on nanotechnology that are currently funded as of November 2018 (Figures 6a and 6b). In addition, the annual funding of NIH R01s focusing on nanotechnology has shown steady increment in the past decade, excluding small drops between 2013 and 2014. Collectively, NIH invests over $200 M per year in nanotechnology research, and many of the institute-specific programs are noted below (Figure 6c).58 It is important to note that many institutes are currently funding nanomedicine research, showing growing interest of academic investigators in the application of nanotechnology toward diseases other than cancer. Here, we did not analyze the funding for biomedical application of nanotechnology from the National Science Foundation, Department of Defense, FDA, other government funding agencies, nonprofit academic associations or private foundations, etc.

6. OUTLOOK AND CONCLUSION The field of cancer nanomedicine is currently undergoing substantial changesshifting away from working against biology and toward working with biology. Many new directions and concepts are emerging, for example, the use of tumorinfiltrating approaches to enhance the penetration of nanomaterials in tumor tissue, structural transformation of nanoparticles N



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will continue to impact the treatment of cancer patients. In addition, the recent investment in biotechnology firms also points to increased interest in using nanotechnology for treatment of other diseases, including ocular, infectious and orphan diseases, as well as for delivery of personalized immunotherapy, will open new avenues for harvesting nanomedicine potential.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Anna Schwendeman: 0000-0002-8023-8080 Notes

The authors declare no competing financial interest. Biographies Dr. Hongliang He received his Ph.D. in pharmaceutics from China Pharmaceutical University. After working as a research scientist at Novartis Pharmaceutical for one and a half years, he joined Virginia Commonwealth University as a Postdoctoral Fellow from December 2015 to July 2018. In August of 2018, he joined the University of Michigan as a research fellow. Currently, his research interests are drug delivery using synthetic high density lipoproteins (HDL), functionalized nanoparticles for targeting atherosclerotic plaques, and cancer nanomedicine. Dr. Lisha Liu obtained her Ph.D. degree in the field of Pharmaceutical Science at Fudan University in 2018. In the same year, she became a visiting scholar at Winship Cancer Institute of Emory University for 6 months. She is currently working as a Postdoctoral Fellow at the University of Michigan. Her research interests focus on development of biomimetic materials for cancer therapy and understanding the mechanisms of biomimetic materials in disease. Dr. Emily E. Morin received her Ph.D. in Pharmaceutical Sciences from the University of Michigan in 2019. She is currently working as a Postdoctoral Fellow in the Vascular Physiology Groupa part of the Department of Cell Biology and Physiologyat the University of New Mexico Health Science Center in Albuquerque, NM. Her research interests include biological mechanisms of vascular disease and vascular-targeted drug delivery strategies. Dr. Min Liu is an Associate Professor in the Department of Pharmaceutical Sciences in the School of Pharmacy at Fudan University. Dr. Liu received her B.S. degree in Pharmacy and M.S. degree in Biochemistry from Sichuan University and Ph.D. in Pharmaceutics from Fudan University. She was promoted to Associate Professor in Pharmaceutical Science at Fudan University in 2007. Her current research interests are targeted drug delivery systems, nonviral gene delivery vehicles, and peptide-based therapeutics delivery. Dr. Anna Schwendeman is an Associate Professor of Pharmaceutical Sciences at the University of Michigan and a member of the multidisciplinary Biointerfaces Institute. She obtained her BS in Physical Chemistry from Moscow Institute of Physics and Technology and PhD in Pharmaceutics from Ohio State University. Dr. Schwendeman worked in biotechnology industry at Esperion Therapeutics, Pfizer and Cerenis Therapeutics for 12 years on translation from discovery to Phase 2 clinical trials of cardiovascular nanomedicines, HDL mimetics. Her current research is on development of novel HDL mimetics for treatment of sepsis, lysosomal storage diseases, and drug and vaccine delivery applications. O


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