Table 1 Summary of non-immune checkpoint blockade agents

Ensituximab

MUC5A

NCT01040000

I/II

CRC and pancreatic

OS improved from 5.0 to 6.8 months, 21/56 pts survived > 12 months

< 2% of patients with grade 3 toxicities and no grade 4 adverse events

Trial completed

CEA CD3 TCB (RG7802, RO6958688)

CEA and CD3

NCT02324257

I

CEA(+) solid tumors

5% PR

16% patients developed grade 3 or more adverse events

In conjunction with obinutuzumab

NCT02650713

I

CEA(+) solid tumors

20% PR

In conjunction with atezolizumab

Blinatumomab

CD19 and CD3

NCT01741792

II

DLBCL

19% CR, PFS up to 20 months

Grade 3 neurologic events (9% encephalopathy, 9% aphasia)

Trial completed

BAY2010112 (AMG212, MT112)

PSMA and CD3

NCT01723475

I

Castration-resistant prostate cancer

Not reported

–

Study is ongoing but not recruiting

MOR209/ES414

PSMA and CD3

NCT02262910

I

–

AFM13

CD30 and CD16A

NCT01221571

I

CD30+ HL

3/26 PR, 13/26 SD, overall DCR 61.5%

Mild to moderate adverse events ranging from fever to infusion reactions

Trial completed

NCT02321592

II

CD30+ HL

–

–

–

ABBV-339

c-Met

NCT02099058

I

NSCLC

19% PR

All-grade adverse events in > 10% of patients

Used in conjunction with erlotinib

Glembatumumab vedotin (GV, CDX-011)

gpNMB

NCT02302339

II

Melanoma

1/62 CR, 6/62 PR, and 33/62 SD

Alopecia, neuropathy, rash, fatigue and neutropenia

–

Losatuxizumab vedotin (ABBV-221)

EGFR

NCT02365662

I

EGFR-dependent tumors

38% SD and 1 patient had unconfirmed PR

Infusion reactions and fatigue

–

Mirvetuximab soravtansine (IMGN853)

Folate receptor alpha (FRα)

NCT01609556 (FORWARD I)

I

Ovarian cancer

ORR 46%

1/37 CR and 16/37 PR

Monotherapy

NCT02606305 (FORWARD II)

I

Ovarian cancer

–

Most adverse events were grade 2 or less

Used in combination with bevacizumab, carboplatin, liposomal doxorubicin, or pembrolizumab

Enfortumab vedotin (ASG-22CE; ASG-22ME)

Nectin-4

NCT02091999

I

Urothelial tumors

ORR 40%, CR 3/68, median duration of response was 18 weeks, and median PFS 17 weeks

85% developed adverse events, but most were grade 2 or less

–

Sacituzumab govitecan (IMMU-132)

Trop-2

NCT01631552

I/II

Epithelial cell tumors

30% ORR, 2/69 CR, 19/69 PR, median OS 16.6 months for triple negative breast cancer

Neutropenia, diarrhea, febrile neutropenia

–

ORR 19%, median

PFS 5.2 months, and a median OS of 9.5 months in NSCLC

Inotuzumab ozogamicin (InO/CMC-544)

CD22

NCT01055496

I

CD22+ NHL

ORR 53%

85% thrombocytopenia, 69% of neutropenia

Used in conjunction with rituximab, gemcitabine, dexamethasone, and cisplatin

Trial completed

Labetuzumab govitecan (IMMU-130)

CEACAM

NCT01605318

II

CRC

1/86 PR, 42/86 had SD, OS was 6.9 months, and PFS was 3.6 months

16% Neutropenia), 9% anemia, and 7% diarrhea

–

Lorvotuzumab mertansine (IMGN901)

CD56

NCT01237678

I/II

SCLC

94 patients (combination ADC with chemotherapy) and 47 patients (no ADC) achieved a PFS of 6.2 and 6.7 months, respectively

Median OS was 10 months in both cohorts

29% Peripheral neuropathy , 21/94 patients had a treatment-emergent adverse event leading to death

Used in combination with carboplatin and etoposide

Rovalpituzumab tesirine (Rova-T)

DLL3

NCT02674568

II

SCLC

18% ORR, and 54% SD

38% developed serious adverse events (pleural and pericardial effusions)

Ongoing

NCT03026166

I

SCLC

–

–

Used in combination with nivolumab or nivolumab and ipilimumab

ADCT-301

CD25

NCT02432235

I

HL and NHL

1/18 CR, 1/18

Rash, mucositis, enteritis, and elevated CPK

-

PR, 6/18 SD

NCT02588092

I

AML and ALL

–

–

–

TAK-264 (MLN0264)

GCC

NCT02202785

II

Pancreatic adenocarcinoma

3% ORR

All patients developed at least 1 adverse event

Trial was terminated

MEDI-4276

HER2

NCT02576548

I/II

HER2+ solid tumors

–

–

–

XMT-1522

HER2

NCT02952729

I

HER2+ breast cancer

–

–

–

ARX-788

HER2

NCT02512237

I

HER2+ c1ancers

–

–

–

DS-8201a

HER2

NCT02564900

I

Solid tumors

–

–

–

SDY985

HER2

NCT02277717

I

Solid tumors

–

–

–

ADCT-502

HER2

NCT03125200

I

HER2+ solid tumors

–

–

–

Glembatumumab vedotin (CDX-011, CR-11-vc-MMAE)

GPNMB

NCT02302339

II

Melanoma

1/62 CR, 6 PR, 33 SD, and median OS was 9.8 months

Alopecia, neutropenia, and rash

–

NCT01156753

II

Advanced GPNMB-expressing breast cancer

ORR 6%

Rash and pruritus

Trial completed

SAR566658

CA-6

NCT01156870

II

Solid tumors expressing CA6

1/114 CR, 8 PR, and 39% SD

Mild toxicities: fatigue, neuropathy, neutropenia

Trial completed

SGN-LIV1A

LIV-1

NCT01969643

I

Breast cancer

ORR 11% and SD or better achieved in 63% of patients

No dose-limiting toxicities

Used in combination with trastuzumab

PF-06647020

Tyrosine kinase 7

NCT02222922

I

Advanced solid tumors

1/76 CR, 5 PR, 12 SD, and 4 PD

Most toxicities were mild: nausea, alopecia, neutropenia

–

PF-6647263

Ephrin-A4

NCT02078752

I

Advanced solid tumors

5/48 PR

Dose-limiting toxicities were observed in 6 patients

Trial completed

SAR428926

LAMP-1

NCT02575781

I

Solid tumors

–

–

–

PCA062

P-cadherin 3

NCT02375958

I

Triple negative breast cancer, head and neck cancer, esophageal cancer

–

–

–

U3-1402

HER3

NCT02980341

I/II

HER3+ metastatic breast Cancer

–

–

–

HuMax-Axl

Axl

NCT02988817

Ovarian, cervical, endometrial, NSCLC, thyroid cancer, and melanoma

–

–

–

MEDI3726

PMSA

NCT02991911

I

Metastatic castration-resistant prostate cancer

–

–

Used in combination with enzalutamide

T4 immunotherapy

ErbB dimers, IL4

NCT01818323

I

HNSCC

DCR 44%

All grade 2 (or less) adverse events

Intratumoral T-4 therapy

CART-19

CD19

NCT01044069

I

B-ALL

CR rates were 95 and 77% on patients with < 5% of blasts in the bone marrow and those with > 5%, respectively

CRS and neurotoxicity

–

NCT02348216

I/II

NHL

ORR 82% and CR 39% after 8 months

31% Febrile neutropenia, 24% thrombocytopenia, 21% encephalopathy, and 13% CRS

Some patients received steroids and others tocilizumab

NCT01865617

I/II

ALL, NHL, and CLL

31/33 ALL patients achieved CR, 6/12 CLL with CR, 84% ORR in NHL

16% CRS and 31% neurotoxicity

All CLL pts had received prior ibrutinib

Anti-GPC3

GPC3

NCT02395250

I

GPC3+ HCC

1/13 with PR

No dose-limiting toxicities

–

CART-133

CD133

NCT02541370

I

HCC, pancreas, CRC, cholangiocarcinoma

21/23 PFS ranging from 8 to 22 weeks

Hyperbilirubinemia and CRS

–

bb2121

BCMA

NCT02658929

I

MM

6/11 ORR

Only grade 1–2 CRS

ORR seen in patients who received higher doses of T cells

Anti-kappa light chain

Kappa light chains

NCT00881920

I

Kappa (+) CLL, NHL, and MM

2/9 CR, 1/9 PR. 4/7 patients with MM had SD

None

–

Anti-CD30

CD30

NCT01316146

I

HL and NHL

2 patients with HL and 1 w/ ALCL achieved CR, 3 patients with HL achieved SD

None

–

NCT02690545

Ib/II

CD30+ HL and NHL

–

–

–

Anti-IL13

IL13Rα2

NCT02208362

I

Glioblastoma

CR in 1 patient

None

–

NY-ESO-1c259t

NY-ESO-1 and HLA-A2

NCT01343043

I/II

Sarcoma

ORR 50%, 1 case of CR

96% Leukopenia, 79% anemia, 79% thrombocytopenia, 1 fatal bone marrow failure, and 11/34 cases with CRS

–

Anti-E6

E6

NCT02280811

I/II

HPV 16+ carcinomas (e.g., cervical, anal, pharyngeal)

2/12 PR

No dose-limiting toxicity

Study completed

Anti-MAGE A10

MAGE-A10

NCT02989064

I

Urothelial cancer, HNSCC, or melanoma

–

–

–

TIL

Varies depending on tumor

NCT01319565

II

Melanoma

CR24%

13/48 patients who received TBI developed thrombotic microangiopathy not seen in patients with no TBI

In combination with TBI

MIL

Varies depending on tumor

NCT00566098

I/II

MM

27% CR, 27% PR, 23% SD, and 14% PD

Not mentioned

Study completed

Coxsackievirus A21 (CVA21–CAVATAK)

ICAM-1-expressing tumors

NCT02565992

Ib

Melanoma, NSCLC, bladder, and prostate cancer

ORR 73% and DCR 91% in melanoma

No dose-limiting toxicities

In combination with pembrolizumab

NCT02043665

NCT02307149

I

Melanoma

ORR 38%

Minimal toxicity

In conjunction with ipilimumab

DCR 88%

Pelareorep (Reolysin)

Different tumors

NCT00984464

II

Melanoma

ORR 21%, 1-year survival 43%, DCR85%

Fever was the most common toxicity

In combination with carboplatin and paclitaxel. Study was completed

NCT01656538

II

Breast cancer

Median OS was 17.4 months for patients with both agents and 10.4 months for patients with paclitaxel alone

Fatigue, nausea, vomiting, diarrhea

In combination with paclitaxel, or paclitaxel alone

DNX-2401

Glioblastoma

NCT01956734

I

Glioblastoma

1 patient was alive 30 months into treatment and 2 after 23 months

Related to temozolamide or underlying disease

In combination with temozolamide

Enadenotucirev (EnAd)

Tumors of epithelial origin

NCT02636036

I

Epithelial tumors

–

–

In combination with nivolumab

HS-110 (Viagenpumatucel-L)

Lung adenocarcinoma cells

NCT02439450

I/IIb

Lung adenocarcinoma

ORR 50%

Injection site reactions, maculopapular rash

In combination with nivolumab

gp96

Gastric cancer cells

NCT02317471

II

Gastric cancer

2-year OS was 81.9% in the vaccination arm vs. 67.9% with chemotherapy-alone arm

No clinically significant adverse events

In combination with oxaliplatin

GM.CD40L

Lung adenocarcinoma cells

NCT02466568

I/II

Lung adenocarcinoma

Median OS was 9.4 months

No dose-limiting toxicities

Some patients had added CCL21 to GM.CD40L

RNA-lipoplex (RNA(LIP))

Melanoma antigens

NCT02410733

I/II

Melanoma

–

No dose-limiting toxicities

–

VXM01

VEGFR-2

EudraCT 2011-000222-29

I

Pancreatic cancer

OS was 9.3 months vs 8.4 months (placebo)

Lymphopenia and increased diarrhea

Oral vaccine

INO-5150

Prostate cancer antigens

NCT02514213

I

Prostate cancer

10% PD

No dose-limiting toxicities

Used with or without IL-12. Study is not recruiting patients

INVAC-1

Human telomerase

NCT02301754

I

Solid tumors

12/20 SD

Asthenia and local reaction at injection site

–

pTVG-HP

PAP

NCT01341652

II

Prostate cancer

–

–

Ongoing

ADXS11-001

E7 antigen

NCT02164461

I

Cervical cancer

–

Only 1 > grade 2 adverse event (hypotension)

Ongoing

AdMA3

MAGE-A3

NCT02285816

I

Solid tumors

Evidence of induction of pro-inflammatory genes and subsequent anti-tumor activity

4/41 patient developed dose-limiting toxicities (hypoxia, dyspnea, vomiting, headache)

Used in conjunction with an oncolytic virus (MG1MA3)

AdHER2ECTM

Her2

NCT01730118

I

Her2(+) tumors

1/27 CR, 1 PR, and 5 SD

Local injection site reactions

–

CMB305

NY-ESO-1

NCT02387125

I

NY-ESO-1-expressing solid tumors

Increase of anti-NY-ESO-1 T cells in 65% of patients and anti-NY-ESO-1 antibodies in 68% of patients

–

–

MVA

Brachyury

NCT02179515

I

Advanced solid malignancies

82% of patients developed brachyury-specific immune responses

No dose-limiting toxicities were observed

Trial completed

BPX101

Human prostate-specific membrane antigen

NCT00868595

I

Prostate cancer

1/18 with CR and 2/18 PR

No dose-limiting toxicities

Trial completed

WT-1

WT-1-expressing tumors

UMIN000005248

II

Pancreatic adenocarcinoma

Increased OS from 21.5 (gemcitabine alone) to 34.2 (gemcitabine with WT-1 vaccine)

–

Used in conjunction with gemcitabine

WT4869

WT-1-expressing tumors

JapicCTI-101374

I/II

MDS

ORR 18.2%, median OS 64.71 weeks

30.8% Neutropenia, 7.7% febrile neutropenia, and 7.7% elevated CPK

Trial completed

Galinpepimut-S

WT-1-expressing tumors

NCT01265433

II

Pleural mesothelioma

PFS 45%, median OS 22.8 months

Mild and not clinically significant

Trial completed

DPX-Survivac

Survivin-expressing tumors

NCT01416038

Ib

Ovarian, fallopian, and peritoneal cancer

Sustained immune responses of varying magnitude and duration

Skin ulceration

Trial completed

AE37

Her2

NCT00524277

II

Her2(+) breast cancer

Disease-free survival improved from 51% (GM-CSF alone) to 89% (AE37+ GM-CSF)

Vaccines is safe and well tolerated

Used with GM-CSF

Multi-HLA binding peptides

HSP70 and GPC3

UMIN000020440

I

Solid tumors

Decreased tumor-marker expression in 6/12 patients and disease control in 5/12 patients

No severe toxicities

–

URLC10-CDCA1-KOC1

URLC10, CDCA1, KOC1

UMIN000003557

II

Esophageal squamous cell carcinoma

No significant difference of relapse-free survival compared to control group, but there was good immunological response

–

–

Poly-ICLC

TLR-3

NCT01984892

I/II

Solid tumors including melanoma, breast, and HNSCC

1/8 SD for 41 weeks; the remainder of patients showed PD

Mild and limited to the site of application

Study was terminated

BO-112

MDA-5 and NOXA

NCT02828098

I

Melanoma and breast cancer

–

1 case of reversible thrombocytopenia

–

IVAC MUTANOME

Personal tumor neoantigens

NCT02035956

I

Melanoma

8/13 patients remained recurrence-free for the entire follow-up period (12–23 months)

No major adverse events

Ongoing

Immunogenic personal neoantigen vaccine

Personal tumor neoantigens

NCT01970358

I

Melanoma

4/6 patients that had no recurrence of the disease at 25 months after vaccination

Mild flu-like symptoms, injection site reactions, rash, and fatigue

–

DS-8273a

TRAIL-R2 (DR-5)

NCT02076451

I

Solid tumors

–

No dose-limiting toxicities

–

Ad-RTS-hIL-12

IL-12

NCT02026271

I

Glioblastoma

Median OS 12.5 months

Flu-like illness, grade 3 CRS, transaminitis

Used in with Veledimex

NKTR-214

IL-2

NCT02983045

I/II

Solid malignancies

1 patient had unconfirmed CR

No dose-limiting toxicities

Used in conjunction with nivolumab

NCT02869295

I/II

Solid malignancies

23% achieved tumor size reduction ranging from 10–30%

No dose-limiting toxicities

–

BMS-986205

IDO

NCT02658890

I

Solid tumors

–

Hepatitis, rash

Used in conjunction with nivolumab

Indoximod

IDO

NCT02073123

II

Melanoma

ORR 52%

No significant toxicities

Used in conjunction with ipilimumab, nivolumab, or pembrolizumab

NCT02077881

II

Pancreatic

ORR 37%

One case of colitis

Used with both gemcitabine and nab-paclitaxel

NCT01560923

II

Prostate

Median PFS increased from 4.1 to 10.3 months

No significant adverse events

–

Epacadostat

IDO

NCT02327078 NCT02178722

I/II

Solid and hematologic malignancies

ORR of 75% (melanoma) and 4% (CRC)

No dose-limiting toxicities

–

MEDI9197

TLR7/8

NCT02556463

I

Solid malignancies

–

Mild adverse events only

In combination with durvalumab and radiation therapy

PG545 (pixatimod, pINN)

TLR9/IL-12

NCT02042781

I

Solid malignancies

SD for 24 weeks, DCR of 38%

Dose-limiting toxicities in 3/23 patients

–

Poly-ICLC

TLR3

NCT00553683

I

HCC

PFS 66% at 6 months, 28% at 24 months

Most grade I–II adverse events

In combination with radiation therapy

OS 69% at 1 year, 38% at 2 years

CB-1158

Arginase

NCT02903914

I

Solid malignancies

–

No dose-limiting toxicities

In conjunction with nivolumab

LTX-315

Tumor mitochondrial membranes

NCT01986426

I

Melanoma and breast cancer

2/28 CR, 5 patients had a decreased of > 50% of the tumor size, and 8 patients achieved SD

Most common adverse events were mild local erythema, flushing, pruritus, and transient hypotension

In combination with ipilimumab or pembrolizumab