PMC0
10.1186%2F1479-5876-8-71
results
No clinically significant local or systemic IMP321-related adverse events were recorded, in line with a previous study in which IMP321 was used alone (i.e. without chemotherapy) [>>13<<]. With the combination therapy, six grade 3 adverse events were recorded (four in the 0.25 mg group and one in the 1.25 mg and 6.25 mg group each): asthenia (3 cases), neuropathy, allergic reaction and neutropenia. In addition, one
The sera from these (and other) patients were then assayed without any dilution in a very sensitive bridging immunogenicity assay using the MSD analyzer [>>15<<]. The tested sera gave a signal below the detection range (2 ng/ml). Repeated injection of IMP321 up to 6.25 mg did not induce anti-IMP321 antibodies.
2 panel B)[>>16<<,17].
2 panel B)[16,>>17<<].
control group is derived from the ECOG 2100 study, the only randomized phase III study with a very similar chemotherapy administration schedule using 90 mg/m2 paclitaxel given on days 1, 8 and 15 every 4 weeks until disease progression [>>18<<]. In the subgroup of patients with measurable disease at inclusion (like our patients) the response rate was 25% (64 patients with partial or complete response out of 254).
Note that the normal range for monocytes is 0.3 - 0.8 × 109 CD45+CD14+ cells/l whole blood [>>19<<] and therefore many patients and especially the poor responders are monocytopenic at D1.
methods
Tumor response and progression were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [>>14<<] with imaging studies done 2 weeks after the sixth and the twelfth injections.
The sera from some patients were also assessed in a bridging immunogenicity assay using the electrochemiluminescence Meso Scale Discovery (MSD) analyzer [>>15<<]. Briefly, any drug-specific antibodies present in undiluted serum samples were captured and revealed by biotin- and SULFO-Tag-conjugated IMP321 respectively, on streptavidin-coated plates.
An anti-LAG-3 mAb (17B4) diluted in neat human AB (Jacques Boy) was used as reference standard (see [>>13<<] for details).
discussion
The resulting T cell immune response contributes to the regression of the tumor [>>20<<]. However, this initial immune response needs to be prolonged and amplified by a T-cell booster that is non-toxic and can be given repeatedly, such as IMP321. IMP321 has a direct effect on APC which express MHC class II giving rise to
IMP321 has a direct effect on APC which express MHC class II giving rise to rapid APC activation and leading to reactivation and expansion of antigen-experienced memory CD8 T cells [>>11<<].
Monocytes are the most common MHC class II+ primary target cells for IMP321 in the blood [>>12<<] and therefore it makes sense that a higher number of monocytes before treatment should favor the tumor response to
We used the weekly, 3 weeks out of 4, chemotherapy regimen which was introduced to reduce cumulative neurotoxicity observed with weekly paclitaxel administration [>>18<<]. Repeated single doses of IMP321 were administered on D2 and D16 of the 28-day paclitaxel cycle, on the day after the chemotherapy, to activate the antigen-loaded APC.
This repeated dose injection protocol has been shown separately to be well tolerated for doses up to 30 mg in advanced cancer patients and to induce CD8 memory T cell expansion [>>13<<].
In the present study, clinical benefit at 6 months was observed for 90% of patients in contrast to less than 50% of patients (PFS = 5.6 months) in the historical control group [>>18<<]. Also the objective response rate of 50% at the post study visit compared favorably to the 25% response rate in the historical control group [18].
Also the objective response rate of 50% at the post study visit compared favorably to the 25% response rate in the historical control group [>>18<<]. Although the inclusion and exclusion criteria were similar, the resulting patient populations were not identical in the two studies. For instance we enrolled older patients (64 years old compared to 55) and more patients with extent of
Late responses are frequent and may even occur after an initial period of tumor progression [>>21<<]. In the present study, for the 15 PR, the tumor regression during maintenance chemotherapy between D85 and D170 was not much less than that seen during induction chemotherapy between D1 and D85. This level of maintained response may be a
The importance of this subset in cancer was highlighted when it was shown for the first time that circulating EMRA cells exert ex vivo tumor-specific cytolytic activity in melanoma patients [>>22<<]. These EMRA cells have been characterized as terminally differentiated CD8 T cells potentially able to home into inflamed tissues such as the tumor microenvironment because they have lost the CD62L and CCR7 lymphoid homing receptors
These EMRA cells have been characterized as terminally differentiated CD8 T cells potentially able to home into inflamed tissues such as the tumor microenvironment because they have lost the CD62L and CCR7 lymphoid homing receptors [>>16<<,17].
These EMRA cells have been characterized as terminally differentiated CD8 T cells potentially able to home into inflamed tissues such as the tumor microenvironment because they have lost the CD62L and CCR7 lymphoid homing receptors [16,>>17<<].
Memory T cells are generated and stored in secondary lymphoid organs, such as lymph nodes, spleen and the bone marrow [>>23<<]. There is a high frequency of memory T cells against breast tumor-associated antigen MHC class I-restricted peptides in the bone marrow of breast cancer patients [24].
There is a high frequency of memory T cells against breast tumor-associated antigen MHC class I-restricted peptides in the bone marrow of breast cancer patients [>>24<<]. Given that it is only after several rounds of proliferation that memory T cells appear in the peripheral blood, it may well be that the significant and sustained increase in EMRA CD8 T cells in the blood of our patients is an indication
We have shown that a long-lived EM subset was increased by IMP321 in renal cell carcinoma patients [>>13<<]. Successful active immunotherapy may depend not upon a transient increase in short-lived effector T cells but rather upon the progressive reinforcement of these vital long-lived effector-memory subsets. If this is true it could explain
If this is true it could explain why successful active immunotherapies exert their effects over years [>>25<<].
In the mouse, paclitaxel can mimic bacterial LPS by activating macrophages and DC [>>26<<]. However this action of paclitaxel on mouse MD-2/TLR4 is in contrast with the observation that paclitaxel associates with human MD-2 in vitro without promoting TLR4 activation [27].
However this action of paclitaxel on mouse MD-2/TLR4 is in contrast with the observation that paclitaxel associates with human MD-2 in vitro without promoting TLR4 activation [>>27<<].
A clinical study indicated that the development of a lymphocytic infiltrate after chemotherapy correlated with a positive response to neoadjuvant paclitaxel therapy [>>3<<]. Like many cytotoxic compounds, paclitaxel may have an immuno-adjuvant effect that relies on the capacity of APC to engulf dying tumor cells and then process and present tumor antigens to memory T cells [20]. However, analyses of PBMC
Like many cytotoxic compounds, paclitaxel may have an immuno-adjuvant effect that relies on the capacity of APC to engulf dying tumor cells and then process and present tumor antigens to memory T cells [>>20<<]. However, analyses of PBMC subsets in patients receiving taxane therapy have not revealed any alterations in these subsets in terms of percentages or phenotypes [28,29].
However, analyses of PBMC subsets in patients receiving taxane therapy have not revealed any alterations in these subsets in terms of percentages or phenotypes [>>28<<,29].
However, analyses of PBMC subsets in patients receiving taxane therapy have not revealed any alterations in these subsets in terms of percentages or phenotypes [28,>>29<<].
is currently used as a surrogate for assessing human APC activation and also as a potency measure of sipuleucel-T, an approved active cellular immunotherapy product designed to stimulate an immune response against prostate cancer [>>25<<,30]. These observations, combined with the lack of any IMP321 side effects, clearly indicate that a 6 mg IMP321 s.
is currently used as a surrogate for assessing human APC activation and also as a potency measure of sipuleucel-T, an approved active cellular immunotherapy product designed to stimulate an immune response against prostate cancer [25,>>30<<]. These observations, combined with the lack of any IMP321 side effects, clearly indicate that a 6 mg IMP321 s.
We have shown separately that increasing the dose from 6 to 30 mg does not seem to increase the immune response in cancer patients [>>13<<].
background
For instance, in breast cancer patients who receive adjuvant chemotherapy, the analysis of metastasis-free survival showed an overall significantly lower percentage of metastasis-free patients in the group with mutated TLR4 [>>1<<]. The effect of the TLR4 mutation is to reduce antigen-presenting cell function. Such patients could not benefit fully from the immunological component of chemotherapy, i.e. the induction of cytotoxic CD8 T cell responses to tumor
A similar observation has been reported more recently in advanced colon cancer treated with oxaliplatin [>>2<<] and further supports the idea that apoptotic cell death induced by chemotherapy leads to a beneficial immunoadjuvant effect [1,3,4].
A similar observation has been reported more recently in advanced colon cancer treated with oxaliplatin [2] and further supports the idea that apoptotic cell death induced by chemotherapy leads to a beneficial immunoadjuvant effect [>>1<<,3,4]. Enhancing such chemotherapy-induced T cell responses by giving a non-specific immunostimulatory factor which induces the antigen presenting cells (APCs) to mature and transport the tumor antigens to the lymph nodes for presentation
A similar observation has been reported more recently in advanced colon cancer treated with oxaliplatin [2] and further supports the idea that apoptotic cell death induced by chemotherapy leads to a beneficial immunoadjuvant effect [1,>>3<<,4]. Enhancing such chemotherapy-induced T cell responses by giving a non-specific immunostimulatory factor which induces the antigen presenting cells (APCs) to mature and transport the tumor antigens to the lymph nodes for presentation to
A similar observation has been reported more recently in advanced colon cancer treated with oxaliplatin [2] and further supports the idea that apoptotic cell death induced by chemotherapy leads to a beneficial immunoadjuvant effect [1,3,>>4<<]. Enhancing such chemotherapy-induced T cell responses by giving a non-specific immunostimulatory factor which induces the antigen presenting cells (APCs) to mature and transport the tumor antigens to the lymph nodes for presentation to T
This therapeutic approach is supported by preclinical studies which have shown synergy between chemotherapy and immunotherapy in carcinomas [>>5<<-8].
The soluble LAG-3Ig fusion protein (or IMP321) is a first-in-class immunopotentiator targeting MHC class II+ APCs [>>9<<-12]. It has been tested in previously-treated advanced renal cell carcinoma patients known to be immunosuppressed and shown to induce an increase in the percentage of circulating activated CD8 T cells and of long-lived effector-memory CD8
and shown to induce an increase in the percentage of circulating activated CD8 T cells and of long-lived effector-memory CD8 T cells in all patients treated by repeated injections over 3 months, without any detectable toxicity [>>13<<]. Importantly, a concentration of only a few ng/mL IMP321 has been shown to be active in vitro on APC, showing the great potency of IMP321 as an agonist of the immune system [13].
Importantly, a concentration of only a few ng/mL IMP321 has been shown to be active in vitro on APC, showing the great potency of IMP321 as an agonist of the immune system [>>13<<].
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