410:. At the six-month endpoint, 90% of patients had experienced a clinical benefit. The overall response rate was 50% based on RECIST criteria, which compared favorably with the 25% response rate observed in patients on paclitaxel monotherapy in the ECOG2100 study. The lead investigators of the chemo-immunotherapy combination trial also noted relevant differences in the two studies' patient groups: the ECOG2100 patients were on average younger than in the chemo-immunotherapy study, and a significantly lower percentage had disease in three or more sites upon entry into the trial.
401:
administered ascending subcutaneous doses of efti on days 2 and 16 of a 28-day cycle of paclitaxel over six cycles. The maximum efti dose was 6.25 mg. Paclitaxel was given on days 1, 8, and 15, meaning that patients were administered efti the day after paclitaxel had killed some tumor cells leading to antigenic tumor debris to be processed by dendritic cells for antigen presentation to CD8+ T cells. There were two notable outcomes to this study:
450:. The study, which began in late 2005, saw the patients administered ascending doses of efti (up to 30 mg per subcutaneous injection) fortnightly for six injections. The drug appeared to work at the two highest doses of 6 mg and 30 mg, with the primary outcomes among the eight patients who received these doses:
518:. This randomized and controlled study, conducted in Paris in 2005 saw 40 healthy subjects immunized with 10 μg of HBsAg, and then given either saline (8 subjects) or ascending doses of efti up to 100 μg (32 subjects). An additional 8 subjects received a conventional Hepatitis B vaccine, the Engerix-B product of
369:, a chemotherapy drug, at doses up to 2 mg. The combination was found to be safe, however no significant differences were observed when comparing pre- and post-treatment levels of monocytes, dendritic cells, and T cells, likely due to sub-optimal dosing. The results of the study were reported online in
428:
in the patients' blood samples when compared with baseline data, with the increase at the six-month mark having a statistical significance in each case. Also, the percentage of PBMCs represented by dendritic cells and terminally differentiated effector memory T cells increased, again with statistical
663:
that efti could induce the maturation of monocyte-derived dendritic cells to produce chemokines and TNF-α, and that, when given with CD40/CD40L, it could induce full functional activation of dendritic cells so that they could produce heightened levels of IL-12. IL-12 is required for the induction of
651:
work with human blood samples the investigators found that efti bound all the circulating dendritic cells and a fraction of MHC class II+ monocytes. Significantly, 92% of samples responded at clinically meaningful levels to a first, short exposure of efti. The investigators contrasted the potency of
400:
who had collaborated with Frédéric
Triebel. This paper demonstrated that the level of serum soluble LAG-3 correlated with improved survival in breast cancer patients whose tumors were estrogen or progesterone receptor-positive. In the study, patients on weekly low-dose paclitaxel (chemotherapy) were
295:
In the AIPAC study efti is administered in combination with paclitaxel to women with HER2 metastatic breast cancer whose disease progressed after endocrine therapy. This Phase IIb trial is a randomized, double-blind, placebo-controlled study aiming to enroll 241 patients. It had an open run-in phase
273:
in different mouse tumor models in 1990. Shortly thereafter in 2001, Triebel formed a biotechnology company called
Immutep SA in order to develop the therapeutic potential of LAG-3. Immutep was acquired by Prima BioMed in 2014 and as a result Eftilagimod alpha became Prima BioMed's lead compound. In
529:
showed a similar T cell response potentiation, this time with 60 healthy subjects being administered
Novartis' Agrippal influenza vaccine. This study, initiated in 2005 and completed in mid-2006, compared the influenza vaccine with the vaccine plus efti at doses up to 100 μg. For subjects that
232:
protein consisting of the four extracellular domains of LAG-3 fused to the Fc region of an IgG1(LAG-3Ig). Efti binds preferentially to a subset of MHC class II molecules that are enriched in lipid rafts and/or composed of stable peptide-MHC II (pMHCII) complexes. On T cells, membrane-anchored LAG-3
330:
In each of the three indications, a first cohort of patients is treated and only if a certain pre-determined number of tumor responses is reached may a second cohort of patients be enrolled. This follows the Simons two-stage design. At the 2019 SITC meeting, Immutep released interim results from
682:
cell line received both GVAX and 0.1 μg of soluble LAG-3, the result was a 7-day median survival advantage (47 to 54 days) over the mice which received only GVAX at day 3. Correlated with this survival data, the investigators noted higher levels of tumor-infiltrating lymphocytes for the
623:, showed that efti could induce an antigen-specific CD8+ T-cell response in human PBMCs – evidenced by the upregulation of T cells that displayed cytotoxic activity and produced Tc1 cytokines. The investigators for this work used influenza matrix protein antigen and the tumor antigens
473:
compared to the lower doses (p=0.016). There was a greater percentage of effector-memory CD8+ T cells (CD45RO, CD45RA- and CD62L-), again, statistically significant compared to the lower doses (p=0.008). And there was an increase in the expression of co-stimulatory molecules
748:, who began producing efti for all trials starting from 2016 onwards. 200-liter batches of efti are accepted for clinical trial use by multiple national agencies including FDA, PEI and MHRA. Recently, it was reported that upscaling to 2000-liter batches has initiated.
348:
in unresectable or metastatic melanoma. The trial is noted as complete on clinicaltrials.gov; final results were published at the 2019 World
Immunotherapy Congress in Basel, Switzerland. No major safety concerns and preliminary safety results were reported.
385:
in breast cancer, whereby chemotherapy creates tumor debris (circulating tumor antigen), and efti increases activation of antigen-presenting cells (APCs) as they take up that debris. This trial arose in part from the findings of a June 2005 online paper in
592:. Later, the same authors showed that soluble LAG-3 could reduce the differentiation of macrophages and dendritic cells from monocytes, suggesting that the positive effect of LAG-3 as a dendritic cell-activator applied to pre-existing dendritic cells.
587:
showed that, in human immature monocyte-derived dendritic cells, efti could induce the production of chemokines that would direct the migration of maturing dendritic cells to lymph nodes. Notably, LAG-3-matured dendritic cells were upregulated for
643:, showed that efti could induce the activation of a large range of human effector T cells, resulting in the production of IFN-γ and TNF-α, among other cytokines. The investigators found that effector and effector-memory, but not naïve or
631:
to verify this CD8+ T cell response. They found that a LAG-3-related adjuvant effect depended on direct activation of antigen-presenting cells. For this paper
Triebel collaborated with scientists at the Instituto Nazionale dei Tumori in
673:
demonstrated that efti at low doses could be used as a T cell adjuvant for cancer vaccines. For this work
Triebel collaborated with Cell Genesys, a cancer vaccine company based in South San Francisco. Cell Genesys' lead product,
331:
their first-line metastatic NSCLC trial before announcing that stage 2 of the trial had officially commenced. In early 2020, Immutep also announced in a press release the continuation of their stage 2 trial in HNSCC.
445:
Immutep's first Phase I study of efti in cancer patients was an open-label study in 21 metastatic renal cell carcinoma patients, with the drug being used as a monotherapy. These patients were known to be
269:, to elucidate LAG-3’s role in the adaptive immune system. Triebel et al. had successfully produced a soluble LAG-3Ig fusion protein by 1995 and subsequently discovered its anti-cancer properties
568:
showed the mechanism of action of efti in inducing maturation and activation of human monocyte-derived dendritic cells, whereby efti binds to MHC class II molecules expressed in plasma membrane
601:
from scientists at the
University of Turin, which included Triebel as a co-author, showed that, in mice, efti could potentiate a DNA vaccine targeting HER2 in a spontaneous breast cancer model.
744:. Immutep worked with Henogen as the contracted manufacturing organization to provide efti for all trials until 2014. Immutep changed their contracted manufacturer to the Shangai-based
433:
The results of this study were reported in
January 2010, and following an oral presentation at the ASCO Annual Meeting in June 2010 the results were published in July 2010 in the
572:
on immature dendritic cells and induces morphological changes such as the formation of dendritic projections, an up-regulation of co-stimulatory molecules, and the production of
296:
with 15 patients being treated and the results were published at the 2018 ASCO annual meeting. The study is ongoing and is expected to show results in the first half of 2020.
488:. 7 of the 8 patients dosed at 6 mg had stable disease at 3 months compared with only 3 of 11 at lower doses. This results had statistical significance (p=0.015).
304:
The INSIGHT Phase I study is investigating the feasibility and safety of different routes of drug delivery (e.g. intra-tumoral, intra-peritoneal, and subcutaneous).
237:(TCR) signaling. Efti – as a soluble LAG-3 protein – is an MHC class II agonist and therefore a dendritic-cell activator, causing increased antigen presentation to
358:
344:
The TACTI-mel Phase I study investigated the safety and potential synergies of efti in combination with the programmed cell death (PD-1) antibody
700:
in Japan in which
Yamaguchi researchers would be combining efti with a peptide vaccine they had developed as a potential therapeutic for
951:
522:. Subjects administered efti had higher levels of HBsAg antibody in their blood as well as higher levels of antigen-specific T cells.
514:
showed that efti could increase T-cell response potentiation in healthy subjects being administered the hepatitis B surface antigen
132:
557:
showed that efti (LAG-3Ig) could function as a vaccine adjuvant when immunizing mice with hepatitis B surface antigen and soluble
683:
combination group, and a higher number of antigen-specific CD8+ T cell responses. There was also a notable IgG1 humoral response.
66:
506:
Immutep conducted two Phase I studies designed to evaluate the safety as well as immune response profile of efti in humans:
589:
323:
Second-line metastatic NSCLC in patients refractory to PD-L1 or PD-1 therapies such as pembrolizumab, nivolumab, avelumab)
209:
457:. The eight patients experienced sustained CD8+ T-cell activation (as measured by percentage of CD8+ T cells expressing
107:
764:
577:
678:, consisted of whole tumor cells genetically modified to secrete GM-CSF. When mice that had been inoculated with the
381:
A 30-patient Phase IIa open-label study in HER2-negative metastatic breast cancer has suggested that efti works as a
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241:. In the absence of antigen presentation via MHC class II molecules, efti reactivates dormant antigen-experienced
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2017, Prima BioMed changed its name to
Immutep to reflect its developmental focus on LAG-3 therapeutics.
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Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T (May 1990).
553:
357:
In April 2009, Immutep announced its involvement in a Phase I study in pancreatic cancer conducted at
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609:
213:
204:
Eftilagimod alpha is in Phase II clinical testing. Currently, the main indications for the drug are
87:
910:
892:
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856:
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729:
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efti with TLR1-9 agonists which, while inducing IL-10, are unable to induce a Tc1 IFN-γ response.
382:
814:
155:
43:
96:
804:
796:
447:
425:
238:
116:
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for "Phase I Study of IMP321 Given Alone or as an Adjuvant to a Reference Flu Antigen" at
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in three distinct and independent cancer indications (following a basket trial design):
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144:
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644:
345:
313:
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Soluble LAG-3 was first established as a dendritic-cell activator in the late 1990s.
242:
229:
224:
Eftilagimod alpha ("efti" in short) is a soluble LAG-3 fusion protein that activates
197:
163:
923:"Immutep and Eddingpharm sign agreement for development of ImmuFact IMP321 in China"
308:
Non-small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC)
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266:
186:
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for "A Randomized Phase I Study of a Hepatitis B Antigen Combined With IMP321" at
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257:, who discovered LAG-3 in 1990, worked through the 1990s at his laboratory at the
31:
393:
366:
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In May 2015, Immutep (Prima Biomed at the time) announced a collaboration with
569:
539:
The years 2000 to 2008 saw a number of demonstrations of efti's effectiveness
190:
437:. The study provided the basis of a new patent filing for Eftilagimod alpha.
717:
558:
362:
800:
855:
for "IMP321 Plus First-line Paclitaxel in Metastatic Breast Carcinoma" at
818:
365:. This 18-patient study evaluated for safety the combination of efti with
312:
In the TACTI-002 Phase II study, efti is administered in combination with
837:
for "Lag-3 and Gemcitabine for Treatment of Advanced Pancreas Cancer" at
659:, again in collaboration with the Instituto Nazionale dei Tumori, showed
628:
421:
417:
873:
for "IMP321 Phase 1 Trial in Metastatic Renal Cell Carcinoma (MRCC)" at
530:
received efti there were higher levels of Th1-type CD4+ T cells in PBMC.
929:
182:
151:
245:, allowing them to recognize their antigen targets at the tumor site.
166:
used to increase an immune response to tumors, and is administered by
17:
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466:
262:
147:
785:"LAG-3, a novel lymphocyte activation gene closely related to CD4"
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713:
633:
624:
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drug being developed by the clinical-stage biotechnology company
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664:
IFN-γ, which in turn is critical for the induction of Th1 cells.
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159:
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showed, in animal models, that efti could immuno-potentiate
287:
As of February 2020, three clinical studies are ongoing:
647:, were induced by efti to a full Tc1 response. In their
196:
in combination immunotherapy with PD-1 treatments (e.g.
185:'chemo-immunotherapy,' that is, combined with standard
377:
Phase IIa study in metastatic breast cancer, 2006-2010
732:, a privately held Chinese pharmaceutical company.
106:
86:
81:
65:
60:
52:
42:
37:
416:. There was a sustained increase in the number of
392:by two researchers at the Centre René Huguenin in
441:Phase Ib study in renal cell carcinoma, 2005-2009
928:(Press release). October 8, 2013. Archived from
712:Immutep granted the rights to efti in mainland
482:(CD27+CD28+, p=0.016; and CD27-CD28+, p=0.014).
95:
512:Journal of Immune Based Therapies and Vaccines
353:Phase I study in pancreatic cancer, 2009-2012
170:. Efti has three intended clinical settings:
8:
30:
772:. Vol. 31. WHO Drug Information. 2017.
178:(in a low, effective dose of ~250 μg)
808:
502:Early proof-of-concept studies, 2005-2007
233:is an inhibitory receptor downregulating
115:
359:Washington University School of Medicine
756:
688:Potential use in a liver cancer vaccine
612:by inducing dendritic cell maturation.
29:
291:Metastatic breast carcinoma (HER2 HR)
214:head and neck squamous cell carcinoma
7:
789:The Journal of Experimental Medicine
510:A March 2007 paper published in the
340:Phase I study in melanoma, 2016-2019
154:. Efti is a soluble version of the
25:
435:Journal of Translational Medicine
414:Increase in relevant cell numbers
639:A September 2007 paper in the
525:An April 2007 online paper in
492:The results were published in
1:
604:A March 2006 online paper in
535:Pre-clinical work, 2000-2008
564:An April 2002 paper in the
320:First-line metastatic NSCLC
973:
655:A March 2008 paper in the
210:non-small cell lung cancer
952:Experimental cancer drugs
583:A February 2003 paper in
551:A June 2000 paper in the
471:statistically significant
371:Investigational New Drugs
335:Completed Clinical Trials
766:Recommended INN: List 78
740:Efti is manufactured in
702:hepatocellular carcinoma
670:Clinical Cancer Research
495:Clinical Cancer Research
283:Ongoing Clinical Studies
261:, in collaboration with
239:cytotoxic (CD8+) T cells
226:antigen-presenting cells
206:metastatic breast cancer
27:Experimental cancer drug
615:An April 2006 paper in
383:chemo-immunotherapeutic
259:Institut Gustave Roussy
903:Clinical trial number
885:Clinical trial number
867:Clinical trial number
849:Clinical trial number
831:Clinical trial number
801:10.1084/jem.171.5.1393
645:central memory T cells
595:A March 2003 paper in
168:subcutaneous injection
935:on February 13, 2015.
667:A June 2008 paper in
657:Journal of Immunology
641:Journal of Immunology
566:Journal of Immunology
554:Journal of Immunology
698:Yamaguchi University
610:therapeutic vaccines
728:in October 2013 to
498:in September 2009.
363:St. Louis, Missouri
135:; development code
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911:ClinicalTrials.gov
893:ClinicalTrials.gov
875:ClinicalTrials.gov
857:ClinicalTrials.gov
839:ClinicalTrials.gov
708:Licensing in China
680:B16 mouse melanoma
455:Activated T cells
448:immunocompromised
326:Second-line HNSCC
156:immune checkpoint
129:Eftilagimod alpha
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32:Eftilagimod alpha
16:(Redirected from
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255:Frédéric Triebel
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694:NEC Corporation
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617:Cancer Research
598:Cancer Research
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627:/MART-1 and
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187:chemotherapy
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97:1800476-36-1
67:Legal status
61:Legal status
56:Efti, IMP321
906:NCT00354263
888:NCT00354861
870:NCT00351949
852:NCT00349934
834:NCT00732082
736:Manufacture
730:Eddingpharm
570:lipid rafts
469:) that was
394:Saint-Cloud
367:gemcitabine
162:. It is an
82:Identifiers
53:Other names
44:Trade names
946:Categories
752:References
220:Background
191:paclitaxel
183:first-line
117:SJ82PK3HWA
88:CAS Number
742:CHO cells
718:Hong Kong
559:ovalbumin
418:monocytes
216:(HNSCC).
158:molecule
661:in vitro
649:in vitro
629:survivin
621:in vitro
619:showed,
541:in vitro
422:NK cells
48:ImmuFact
819:1692078
810:2187904
625:Melan-A
606:Vaccine
585:Vaccine
545:in vivo
527:Vaccine
271:in vivo
249:History
152:Immutep
143:) is a
817:
807:
726:Taiwan
467:HLA-DR
263:INSERM
189:(e.g.
148:cancer
137:IMP321
18:IMP321
933:(PDF)
926:(PDF)
770:(PDF)
722:Macao
714:China
578:TNF-α
574:IL-12
516:HBsAg
398:Paris
396:near
160:LAG-3
815:PMID
724:and
696:and
676:GVAX
590:CCR7
576:and
543:and
480:CD28
478:and
476:CD27
463:CD38
459:CD69
265:and
141:efti
108:UNII
805:PMC
797:doi
793:171
361:in
230:kDa
181:as
139:or
133:INN
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