Eftilagimod alpha

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Eftilagimod alpha is a large molecule cancer drug being developed by the clinical stage biotechnology company Immutep (Nasdaq: IMMP). The drug is Immutep's lead compound.

Eftilagimod alpha (lab name: IMP321) [1] is soluble version of the immune checkpoint molecule LAG3, used to increase an immune response to tumours. The drug is administered by subcutaneous injection. Eftilagimod alpha has two intended clinical settings, 'low dose' (for example 250 µg) as adjuvant to cancer vaccines and 'high dose' (such as 12 injections of 6 mg each) as first-line 'chemo-immunotherapy', that is, combined with standard chemotherapy. Eftilagimod alpha has been and is in Phase II clinical testing. The product has been shown to be non-immunogenic, that is, no anti-IMP321 antibodies have been detected in clinical trials.[2] Currently the main indication for the drug is metastatic breast cancer.

Background[edit]

Eftilagimod alpha is a 200 kDA soluble dimeric recombinant fusion protein of the extracellular portion of LAG3 with immunoglobulin, designed to activate antigen presenting cells. LAG3 is expressed on various cells in the immune system including activated T cells, Natural Killer cells (NK cells), B cells and dendritic cells, being a ligand for MHC class II molecules. On T cells LAG-3 is an inhibitory receptor. However, on dendritic cells LAG-3 is an activator, causing increased antigen presentation to cytotoxic CD8+ T cells when it binds to MHC Class II. Eftilagimod alpha is designed to harness this activation capacity as a 'chemo-immunotherapeutic', increasing antigen presentation in the wake of tumor debris created by chemotherapy.

History[edit]

Soluble LAG3 was first established as a dendritic cell activator in the late 1990s. Frédéric Triebel, who discovered LAG3 in 1990,[3] worked through the 1990s at his laboratory at the Institut Gustave Roussy, in collaboration with INSERM and Merck Serono, to elucidate LAG-3’s role in the immune system. Triebel et al. had successfully produced a soluble fusion protein of LAG3 and immunoglobulin around 1995[4] and had initially envisaged its use as an immunosuppressant after evidence that its interaction with MHC class II molecules leads to the down-regulation of CD4+ antigen-specific T cell clone proliferation and cytokine secretion,[5] and that it inhibited the alloresponses of naive peripheral blood lymphocytes.[6] However, in March 1999 a key paper in the Journal of Immunology from scientists at the University of Montreal, on which Triebel was listed as a co-author, demonstrated soluble LAG3's role as a dendritic cell activator.[7] Shortly after this, in 2001, Triebel formed a biotechnology company called Immutep SA in 2001 in order to develop the therapeutic potential of LAG3 including soluble LAG3. Immutep called its product 'ImmuFact IMP321', the 'act' part of ImmuFact referring to the products immune activating properties. By 2010 there was a large body of evidence of the efficacy of IMP321 in cancer.[8] Immutep was acquired by Prima BioMed in 2014 and as a result IMP321 became Prima BioMed's lead compound. In 2017 Prima Biomed changed its name to Immutep as consequence of their developmental Focus on LAG-3 based products.

Pre-clinical work, 2000–2008[edit]

The years 2000 to 2008 saw a number of demonstrations of IMP321's effectiveness in vitro and in vivo.

  • A June 2000 paper in the Journal of Immunology showing that IMP321 would act as a vaccine adjuvant when immunizing mice with hepatitis B surface antigen and soluble ovalbumin.[9]
  • An April 2002 paper in the Journal of Immunology showed the mechanism of action in IMP321 in inducing maturation and activation of human monocyte-derived dendritic cells, where the IMP321 binds to MHC class II molecules expressed in plasma membrane lipid rafts 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 IL-12 and TNF-α.[10]
  • A February 2003 paper in the journal Vaccine showed that, in human immature monocyte-derived dendritic cells, IMP321 could induce production of the chemokines that would direct the migration of maturing dendritic cells to lymph nodes. Notably, LAG-3-matured dendritic cells were upregulated for CCR7.[11] Later, the same authors showed that soluble LAG-3 would reduce the differentiation of macrophages and dendritic cells from monocytes, suggested that the positive effect of LAG-3 as a dendritic cell activator related to existing dendritic cells.[12]
  • A March 2006 online paper in Vaccine showed, in animal models, that IMP321 could immunopotentiate therapeutic vaccines by inducing dendritic cell maturation.[14]
  • An April 2006 paper in Cancer Research showed, in vitro, that IMP321 would induce an antigen-specific CD8+ T-cell response in human PBMCs, with the T cells thus created being cytotoxic and capable of producing Tc1 cytokines. The investigators for this work used influenza matrix protein antigen and the tumor antigens Melan-A/MART-1 and survivin when seeking 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 Istituto Nazionale dei Tumori in Milan.[15]
  • A September 2007 paper in the Journal of Immunology, showing that IMP321 could induces 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 naive or central memory T cells could be induced by IMP321 to a full Tc1 response. In their in vitro work with human blood samples the investigators found that IMP321 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 IMP321. The investigators contrasted the potency of IMP321 with TLR1-9 agonists which, by inducing IL-10, are unable to induce a Tc1 IFN-γ response.[16]
  • A March 2008 paper in the Journal of Immunology, again in collaboration with the Instituto Nazionale dei Tumori, showing in vitro that IMP321 could induce the maturation of monocyte-derived dendritic cells to produce chemokines and TNF-α, and that, when it was given with CD40/CD40L, it could induce full functional activation of such dendritic cells so that they could produce high levels of IL-12. That cytokine is required for the induction of IFN-γ, which in turn is critical for the induction of Th1 cells.[17]
  • A June 2008 paper in Clinical Cancer Research demonstrated that IMP321 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. That company's lead product, called GVAX, was whole tumor cells genetically modified to secrete GM-CSF.[18] When mice that had been inoculated with the B16 mouse melanoma cell line received both GVAX and only 0.1 μg of soluble LAG-3, the result was a 7-day median survival advantage (47 days to 54) for the mice that got both, over those which just received GVAX at day 3. Correlated with this survival, the investigators noted higher levels of tumor-infiltrating lymphocytes for the combination group, and a higher number of antigen-specific CD8+ T cell responses. There was also a notable IgG1 humoral response.[19][20]

Clinical trials[edit]

Early proof-of-concept studies, 2005-2007[edit]

Immutep conducted two Phase I studies with IMP321 designed to evaluate the safety as well as immune response profile of IMP321 in humans

  • A March 2007 paper in the Journal of Immune Based Therapies and Vaccines, showed that IMP321 could increase T cell response potentiation in healthy subjects being administered the hepatitis B surface antigen HBsAg. This randomised and controlled study, conducted in Paris in 2005 (ClinicalTrials.gov identifier NCT00354861, Immutep code name P002), saw 40 people immunized with 10 μg of HBsAg, and then given either saline (8 subjects) or ascending doses of IMP321 up to 100 μg (32 subjects). An additional 8 subjects received a conventional Hepatitis B vaccine, the Engerix-B product of GlaxoSmithKline. Subjects who got IMP321 had higher levels of HBsAg antibody in their blood as well as higher levels of antigen-specific T cells[21]
  • An April 2007 online paper, in Vaccine, showed a similar T cell response potentiation, this time with 60 subjects being administered Novartis' Agrippal influenza vaccine (ClinicalTrials.gov identifier NCT00354263, Immutep code name P001). This study, initiated in 2005 and completed in mid-2006,[22] compared the influenza vaccine with the vaccine plus IMP321 at doses up to 100μg. For subjects that received IMP321 there were higher levels of Th1-type CD4 T cells in PBMC.[23]

Phase Ib study in renal cell carcinoma, 2005-2009[edit]

Immutep's first serious clinical study of IMP321 was an open label study in 21 metastatic renal cell carcinoma patients, with the drug being used as a monotherapy (ClinicalTrials.gov identifier NCT00351949, Immutep code name P003). These patients were known to be immunocompromised. The study, which initiated in late 2005[24] saw patients administered ascending doses of IMP321 up to 30 mg per injection fortnightly for six injections subcutaneously. The drug appeared to work at the two highest doses of 6 mg and 30 mg, with two notable outcomes for the eight patients who received these doses:

  • Activated T cells. The 8 patients experienced a sustained CD8+ T-cell activation (as measured by percentage of CD8+ cells expressing CD69, CD38 and HLA-DR) that was statistically significant compared to the lower doses (p=0.016). There was a greater percentage of effector-memory CD8 T cells (CD45ROhi, CD45RA- and CD62L-), again, statistically significant compared to the lower doses (p=0.008). And there was an increase in the costimulation molecules CD27 and CD28 (CD27+CD28+, p=0.016; and CD27-CD28+, p=0.014).
  • Stable disease. 7 of the 8 patients dosed at 6 mg had stable disease at 3 months compared with only 3 of 11 at lower dose. This result had statistical significance (p=0.015).

The results were published online in the journal Clinical Cancer Research in September 2009.[25]

Phase IIa study in metastatic breast cancer, 2006-2010[edit]

A 30-patient Phase IIa open label study in HER2-negative metastatic breast cancer (ClinicalTrials.gov identifier NCT00349934, Immutep code name P005) has suggested that IMP321 works as a chemo-immunotherapeutic in breast cancer, where chemotherapy creates tumor debris, and IMP321 increases activation of APCs as they take up that debris. This trial arose in part from the findings of a June 2005 online paper in the journal Cancer Letters by two researchers at the Centre René Huguenin in Saint-Cloud near Paris who had collaborated with Frédéric Triebel. That paper demonstrated that soluble LAG3 correlated with improved survival in breast cancer patients whose tumors were estrogen or progesterone receptor positive.[26] The Phase IIa study which partly confirmed this finding was initiated by Immutep around August 2006[27] and was conducted at the René Huguenin as well as two other Paris hospitals - the Hôpital Européen Georges-Pompidou (15th arrondissement) and the Hôpital Tenon (20th arrondissement). In the study, patients on paclitaxel were administered ascending subcutaneous doses of IMP321 on days 2 and 16 of a 28-day cycle of paclitaxel over six cycles. The maximum IMP321 dose was 6.25 mg. Paclitaxel was given on days 1, 8 and 15, meaning patients got IMP321 the day after paclitaxel had created tumor debris. There were two notable outcomes to this study:

  • Response rate. At the six-month measurement point the response rate according to the RECIST criteria was 50%. The study investigators argued that this compared favorably with a 25% rate registered for paclitaxel in another study called ECOG2100, which had the same dosing regiment for paclitaxel but where the response rate for patients with measurable disease at inclusion was only 25%.[28] Some 90% of patients experienced clinical benefit because at the six-month endpoint only 3 patients had progressive disease. The investigators also noted that the patients in their trial were older and there were a significantly greater percentage of patients that had disease in three or more sites than was the case in the ECOG2100 study.
  • Increase in relevant cell numbers. There was a sustained increase in the number of monocytes, NK cells and activated CD8+ T cells in the patient's blood samples, compared to baseline, with the increase at the six-month mark having 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 significance.

The results of this study were reported in January 2010,[29] and following an oral presentation at the ASCO Annual Meeting in June 2010[30] the results were published in July 2010 in the Journal of Translational Medicine.[31] The study provided the basis of a new patent filing for IMP321 .[32]

Phase I study in pancreatic cancer, 2009-2012[edit]

In April 2009 Immutep announced its involvement in a Phase I study in pancreatic cancer conducted at Washington University School of Medicine in St. Louis.[33] This 18-patient study (ClinicalTrials.gov identifier NCT00732082, Immutep code name P008) evaluated for safety the combination of IMP321 with gemcitabine 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 to T cells, probably due to sub-optimal dosing. The results of the study were reported online in the journal Investigational New Drugs in August 2012.[34]

Phase I studies in metastatic melanoma, 2006-2014[edit]

In September 2006 Immutep announced its involvement in a Phase I study being conducted at the Cancer Centre at the St Luc University Clinic in Brussels.[35] This 20-patient study (ClinicalTrials.gov identifier NCT00365937, Immutep code name P006) was a randomised open-label four-arm trial comparing a selected set of 8 HLA-A2 melanoma peptide antigens with or without IMP321 and/or Montanide ISA 51, a vaccine adjuvant composed of a light mineral oil and a surfactant system designed to make a water-in-oil emulsion. In this study all patients randomized in the peptides-alone arm relapsed during the first year whereas a majority of patients in the three other groups were still disease-free at follow-up, when the median disease-free survival follow-up was 33 months. The results of this study were presented to the 25th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer in Washington, DC in October 2010.[36]

In August 2007 Immutep announced its involvement in a Phase I study being conducted at the University Hospital of Lausanne in Switzerland where a group was working on adoptive T cell transfer after transient lymphodepletion associated with peptide vaccination.[37] This study recruited 12 patients (ClinicalTrials.gov identifier NCT00324623, Immutep code name P007) where the patient's lymphocytes were depleted using chemotherapy, after which patients were given their own peripheral mononuclear cells, enriched with tumour-specific CD8 T cells. During the immune reconstitution period the patients were given a cancer vaccine containing a peptide melanoma antigen called MART1, adjuvanted with incomplete Freund’s adjuvant and, in half the patients, IMP321. While there was no confirmed responses as per the RECIST criteria for the 12 patients recruited, the investigators noted a significant expansion of MART-1-specific CD8 T cells in the IMP321 group, where there was also a higher proportions of effector cells and a significantly reduced expansion of regulatory T cells. These results were published in the Journal of Translational Medicine in April 2014.[38]

A third melanoma trial, also at the University Hospital of Lausanne (ClinicalTrials.gov identifier NCT01308294, Immutep code name P009) was designed to assess the effectiveness of IMP321 when combined with the melanoma peptides NA-17, MAGE-3.A2, NY-ESO-1, Melan-A and MAGE-A3-DP4.[39] This study has been terminated due to a low enrollment rate and has not reported any data.

Phase I/II prostate cancer study, 2010 -[edit]

In 2010 scientists at the Istituto Nazionale dei Tumori initiated a 20-patient open label study in prostate cancer patients that combined peptides from survivin with IMP321 (EudraCT Number 2009-017798-39, Immutep code name P010). The peptides, restricted for different HLA-I alleles, are emulsified in Montanide ISA 51. This study has yet to report any data.

Ongoing clinical studies[edit]

As of October 2018 three clinical studies are ongoing.

In the AIPAC study [40] IMP321 is administered in combination with Paclitaxel to woman with HER2-negative metastatic breast cancer who progressed after endocrine therapy. This Phase IIb trial is a randomized, double-blind placebo-controlled study aiming to enroll 241 patients.

The TACTImel Phase I study [41] is investigating safety and possible synergies with the anti-programmed cell death antibody pembrolizumab in unresectable or metastatic melanoma.

The INSIGHT Phase I study [42] is investigating feasibility and safety of different routes of drug application (e.g. intra tumoral, intra peritoneal and sub cutaneous).

Potential synergy with checkpoint inhibitors[edit]

Prima (now Immutep) announced in late May 2015 that it had filed a provisional patent application over the use of IMP321 in combination with immune checkpoint inhibitors, following on from pre-clinical work showing higher response rates from the combinations.[43]

Potential use in a liver cancer vaccine[edit]

In May 2015 Prima announced a collaboration with NEC Corporation and Yamaguchi University in Japan in which Yamaguchi researchers will be combining IMP321 with a peptide vaccine they have developed as a potential therapeutic for hepatocellular carcinoma.[44]

Licensing in China[edit]

Immutep granted the rights to IMP321 in mainland China, Hong Kong, Macao and Taiwan in October 2013 to Eddingpharm, a privately held Chinese pharmaceutical company.[45]

Manufacture[edit]

IMP321 is manufactured in CHO cells. Immutep worked with Lonza in 2012 on cell line selection, master cell banking and process development for IMP321[46] after which the Shanghai-based WuXi PharmaTech was retained as contract manufacture.[47]

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  39. ^ Immunotherapy of HLA-A2 Positive Stage II-IV Melanoma Patients (LAG-3/IMP321)
  40. ^ https://clinicaltrials.gov/ct2/show/NCT02614833?term=AIPAC&recrs=ab&rank=1
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