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DRUG:

lorukafusp alfa (APN301)

i
Other names: ch14.18-IL2, EMD 273063, monoclonal antibody ch14.18 interleukin-2 fusion protein, APN301, APN 301, hu14.18-IL2
Associations
Company:
Apeiron Biologics
Drug class:
IL-2 stimulant, GD2 ganglioside inhibitor
Related drugs:
Associations
2ms
A534260: IT-hu14.18-IL2 With Radiation, Nivolumab and Ipilimumab for Melanoma (clinicaltrials.gov)
P1/2, N=61, Suspended, University of Wisconsin, Madison | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2024 --> Aug 2025
Trial completion date • Trial primary completion date • IO biomarker • Metastases
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IL2 (Interleukin 2)
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PD-L1 expression
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Opdivo (nivolumab) • Yervoy (ipilimumab) • lorukafusp alfa (APN301)
6ms
Evaluation of a Combinatorial Immunotherapy Regimen That Can Cure Mice Bearing MYCN-Driven High-Risk Neuroblastoma That Resists Current Clinical Therapy. (PubMed, J Clin Med)
First, we demonstrate that 9464D-GD2 is nonresponsive to a preferred salvage regimen: anti-GD2 with temozolomide and irinotecan. Second, we have previously shown that adding agonist anti-CD40 mAb and CpG to a regimen of radiotherapy, anti-GD2/IL2 immunocytokine and anti-CTLA-4, cured a substantial fraction of mice bearing small 9464D-GD2 tumors; here, we further characterize this regimen by showing that radiotherapy and hu14.18-IL2 are necessary components, while anti-CTLA-4, anti-CD40, or CpG can individually be removed, and CpG and anti-CTLA-4 can be removed together, while maintaining efficacy. We have developed and characterized a regimen that can cure mice of a high-risk neuroblastoma that is refractory to the current clinical regimen for relapsed/refractory disease. Ongoing preclinical work is directed towards ways to potentially translate these findings to a regimen appropriate for clinical testing.
Preclinical • Journal
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MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • IL2 (Interleukin 2)
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MYCN amplification
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temozolomide • irinotecan • lorukafusp alfa (APN301)
11ms
NK cells propagate T cell immunity following in situ tumor vaccination. (PubMed, Cell Rep)
In a phase I clinical trial, administration of 3xTx (with an immunocytokine fusion of tumor-specific antibody and IL-2, hu14.18-IL2) to subjects with metastatic melanoma increases peripheral CD8 T cell effector polyfunctionality...NK cell depletion increases T infiltration, diminishing CD8 T cell-dependent antitumor response. These findings demonstrate that NK cells sustain and propagate CD8 T cell immunity following 3xTx.
Journal • IO biomarker
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CD8 (cluster of differentiation 8) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • IL2 (Interleukin 2) • CD86 (CD86 Molecule) • NKG2D (killer cell lectin like receptor K1)
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lorukafusp alfa (APN301)
1year
Cyclophosphamide augments the efficacy of in situ vaccination in a mouse melanoma model. (PubMed, Front Oncol)
We have previously shown that an intratumoral (IT) injection of the hu14.18-IL2 immunocytokine (IC), an anti-GD2 antibody linked to interleukin 2, can serve as an in situ vaccine and synergize with local radiotherapy (RT) to induce T cell-mediated antitumor effects. Cured mice developed immunological memory as they were able to reject B78 tumor rechallenge. Taken together, these preclinical results show that CY can augment the antitumor efficacy of IT- IC, given alone or in combination with local RT, suggesting potential benefit in clinical testing of these combinations.
Preclinical • Journal
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CD8 (cluster of differentiation 8) • IL2 (Interleukin 2)
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cyclophosphamide • lorukafusp alfa (APN301)
over1year
CD4 T cell-driven response to immunotherapy against mouse melanoma tumors (AACR 2023)
Using an in situ vaccine (ISV) regimen that includes a combination therapy of radiation (given at D0) with hu14.18-IL2 immunocytokine [anti-GD2 linked to IL2, (Anyxis Immuno-Oncology GmbH (Austria)); given at D5-D9], we can cure mice of large B78 melanoma tumors (B78s)...MHCII expression on tumors can directly engage CD4 cytotoxic T cells, suggesting an important role in the response to immunotherapy for CD4 T cells in melanoma tumors that express MHCII. Understanding the cellular and molecular mechanisms involved in the ISV-induced immune recognition and destruction of B78 may guide future improvements of this clinically-relevant immunotherapy regimen.
Preclinical • IO biomarker
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CD4 (CD4 Molecule) • IL2 (Interleukin 2)
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IFNG expression • MHC-II expression
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lorukafusp alfa (APN301)
over1year
In vivo multiphoton autofluorescence imaging is sensitive to CD8 T cell and tumor cell metabolic changes during immunotherapy in a murine melanoma model (AACR 2023)
This therapy includes external beam radiation, intratumoral hu14.18-IL2 immunocytokine (anti-GD2 mAb fused to IL2, provided by Anyxis Immuno-Oncology GmbH of Vienna, Austria), and intraperitoneal anti-CTLA-4 leading to in situ vaccination and cure of GD2+ murine tumors... These results show that in vivo metabolic imaging enables single cell quantification of metabolic changes in tumor and immune cells during therapy. Combined with other traditional assays, we can elucidate key immune cell populations and the crucial timepoints during therapy where changes are occurring. With continued efforts, this imaging platform may be leveraged to develop new combinations of immunotherapies.
Preclinical • Tumor cell
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CD8 (cluster of differentiation 8) • IL2 (Interleukin 2)
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lorukafusp alfa (APN301)
over1year
Stimulation of natural killer cells with small molecule inhibitors of CD38 for the treatment of neuroblastoma. (PubMed, Chem Sci)
Additionally, we have illustrated that NK cells exhibited enhanced cytotoxicity toward NB cells (14% reduction of NB cells over 90 minutes) when given a combination treatment of our inhibitor and the immunocytokine ch14.18-IL2. Herein we describe the synthesis and biological evaluation of small molecule CD38 inhibitors and demonstrate their potential utility as a novel approach to NB immunotherapy. These compounds represent the first examples of small molecules that stimulate immune function for the treatment of cancer.
Journal • IO biomarker
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IFNG (Interferon, gamma)
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lorukafusp alfa (APN301)
almost2years
Radiation to all macroscopic sites of tumor permits greater systemic antitumor response to in situ vaccination. (PubMed, J Immunother Cancer)
We report a novel use for low-dose RT, not as a direct antitumor modality but as an immunomodulator capable of driving and expanding antitumor immunity against metastatic tumor sites following ISV.
Journal
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CD8 (cluster of differentiation 8) • IL2 (Interleukin 2)
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lorukafusp alfa (APN301)
2years
Administration of intratumoral hu14.18-IL2 immunocytokine and local radiation therapy to activate immune rejection of spontaneous canine melanoma (SITC 2022)
A 9-marker multi-color immunophenotyping panel for flow cytometry (CD3, CD5, CD4, CD8, CD14, CD21, CD25, FoxP3, and PD-1) was optimized using cryopreserved healthy canine PBMC and will be used to assay PBMC from pre and post-treatment timepoints for the protocol treatment dogs. Conclusions IT-IC in combination with local RT in canine melanoma is safe and has antitumor activity with potential to inform clinical development of IT-IC in melanoma patients.
PD(L)-1 Biomarker • IO biomarker
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CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • IL2RA (Interleukin 2 receptor, alpha) • IL2 (Interleukin 2) • CD5 (CD5 Molecule) • CD14 (CD14 Molecule) • FOXP3 (Forkhead Box P3)
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lorukafusp alfa (APN301)
2years
Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Expanded Haploidentical NK Cells and Hu14.18-IL2 (clinicaltrials.gov)
P1, N=0, Withdrawn, University of Wisconsin, Madison | Trial completion date: Sep 2025 --> Sep 2022 | Suspended --> Withdrawn | Trial primary completion date: Sep 2024 --> Sep 2022
Preclinical • Trial completion date • Trial withdrawal • Trial primary completion date
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IL2 (Interleukin 2)
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lorukafusp alfa (APN301)
2years
Anti-GD2 antibodies conjugated to IL15 and IL21 mediate potent anti-tumor cytotoxicity against neuroblastoma. (PubMed, Clin Cancer Res)
Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing NB.
Journal
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CD8 (cluster of differentiation 8) • IL15 (Interleukin 15) • IL21 (Interleukin 21)
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lorukafusp alfa (APN301)
over2years
Mechanism of effective combination radio-immunotherapy against 9464D-GD2, an immunologically cold murine neuroblastoma. (PubMed, J Immunother Cancer)
Treatment with CAIR cures 9464D-GD2 tumors in a NK cell dependent manner and induction of MHC-I by tumors cells was associated with decreased efficacy. These results demonstrate that the early tumor response to this regimen is T and NK cell independent, but that NK cells have a role in generating lasting cures in the absence of MHC-I expression by tumor cells. Further strategies to better inhibit tumor outgrowth in this setting may require further NK activation or the ability to engage alternative immune effector cells.
Preclinical • Journal • IO biomarker
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IFNG (Interferon, gamma) • IL2 (Interleukin 2)
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IFNG expression
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lorukafusp alfa (APN301)
over2years
Combining Immunotherapies with Conventional Cancer Therapies in a Preclinical Model of Treatment-Resistant, High-Risk Neuroblastoma (IMMUNOLOGY 2022)
Here we aimed to test if the clinically-approved salvage therapy of temozolomide and irinotecan (T/I) and αGD2-based therapy replicated human trials and to test if CAIR can be reduced to improve relevance. For chemo studies, mice were treated T/I and αGD2 immunocytokine (Hu14.18-IL2)...In contrast, CAIR can cure 9464D-GD2 bearing mice, and our data indicate that this regimen can be further reduced without decreasing efficacy. A reduced regimen enhances both clinical relevance and our ability to add additional agents to further improve survival.
Preclinical
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IL2 (Interleukin 2)
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temozolomide • irinotecan • lorukafusp alfa (APN301)
almost3years
Discovery and development of NK cell immunostimulatory small molecule CD38 inhibitors for the treatment of neuroblastoma (ACS-Sp 2022)
Additionally, we have illustrated that NK cells exhibited enhanced cytotoxicity toward NB cells (14% reduction of NB cells over 90 minutes) when given a combination treatment of our inhibitor and the immunocytokine ch14.18-IL2. In this presentation, the synthesis and biological evaluation of small molecule inhibitors specifically for use in NB immunotherapy will be described.
IO biomarker
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IFNG (Interferon, gamma)
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lorukafusp alfa (APN301)
3years
Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2 Murine Neuroblastoma. (PubMed, Front Immunol)
On days +14-16, mice were treated with the anti-GD2 immunocytokine hu14.18-IL2...Using allogeneic HSCT for NBL is a viable platform for immunocytokines and ex vivo activated NK cell infusions, but must be balanced with induction of CRS. Regulation of TNFα or activating NK subsets may be needed to improve GVT effects.
Preclinical • Journal
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TNFA (Tumor Necrosis Factor-Alpha) • IL2 (Interleukin 2)
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lorukafusp alfa (APN301)
over3years
Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Expanded Haploidentical NK Cells and Hu14.18-IL2 (clinicaltrials.gov)
P1, N=6, Suspended, University of Wisconsin, Madison | Trial completion date: Sep 2021 --> Sep 2025 | Trial primary completion date: Sep 2021 --> Sep 2024
Preclinical • Trial completion date • Trial primary completion date
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IL2 (Interleukin 2)
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lorukafusp alfa (APN301)
over3years
Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting. (PubMed, PLoS One)
The combination of external beam radiotherapy, intratumoral immunocytokine, and targeted radionuclide immuno-radiotherapy known to have activity against syngeneic melanoma in murine models is feasible and well tolerated in companion dogs with advanced stage, spontaneously arising melanoma or osteosarcoma and has immunomodulatory potential. Further studies evaluating the dose-dependent immunomodulatory effects of this immuno-radiotherapy combination are currently ongoing.
Clinical • Journal
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IL2 (Interleukin 2)
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90Y-NM600 • lorukafusp alfa (APN301)
over3years
[VIRTUAL] Phase I/II trial of intratumoral administration of hu14.18-IL2, with local radiation, nivolumab, and ipilimumab in subjects with advanced melanoma. (ASCO 2021)
Key inclusion criteria: 1) histologically proven, malignant melanoma that is advanced (Stage IV) or surgically incurable; 2) at least 1 (preferably 2) sites of disease amenable to safe repeated IT injections; and 3) must have received or declined at least one FDA approved therapy, either in the adjuvant setting or for metastatic disease, with an impact on survival . Two subjects have been accrued into Phase IA as of 2-4-2021.
Clinical • P1/2 data • PD(L)-1 Biomarker
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IL2 (Interleukin 2)
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Opdivo (nivolumab) • Yervoy (ipilimumab) • lorukafusp alfa (APN301)
over3years
Depth of tumor implantation affects response to in situ vaccination in a syngeneic murine melanoma model. (PubMed, J Immunother Cancer)
When tumors reached 190-230 mm, they were grouped into a 'wave' and treated with our previously published ISV regimen (12 Gy local external beam radiation and intratumoral hu14.18-IL2 immunocytokine)...These data indicate that the physical 'fixed' versus 'mobile' characterization of the tumors may be one simple method of ensuring homogeneity among implanted tumors prior to initiation of treatment. Overall, this short report demonstrates that small differences in depth of tumor implantation can translate to differences in response to immunotherapy, and proposes a simple physical examination technique to ensure consistent tumor depth when conducting implantable tumor immunotherapy experiments.
Preclinical • Journal
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IL2 (Interleukin 2)
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lorukafusp alfa (APN301)
4years
Intratumoral injection reduces toxicity and antibody-mediated neutralization of immunocytokine in a mouse melanoma model. (PubMed, J Immunother Cancer)
Intratumoral injection may be a means of overcoming ADA neutralization of therapeutic activity of tumor-reactive mAbs or ICs and may reduce systemic toxicity, which could have significant translational relevance.
Journal
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IL2 (Interleukin 2)
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lorukafusp alfa (APN301)
over4years
In situ vaccination at a peripheral tumor site augments response against melanoma brain metastases. (PubMed, J Immunother Cancer)
ISV augmented response to ICIs in murine melanoma at brain and extracranial tumor sites. Although baseline tumor-immune microenvironments were similar at brain and extracranial tumor sites, response to ISV+α-CTLA-4 was divergent with reduced infiltration and activation of immune cells in brain tumors. Additional therapies may be needed for effective antitumor immune response against melanoma brain metastases.
Journal
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CD8 (cluster of differentiation 8) • IL2 (Interleukin 2) • FOXP3 (Forkhead Box P3)
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lorukafusp alfa (APN301)
over4years
Preclinical • Trial suspension
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IL2 (Interleukin 2)
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lorukafusp alfa (APN301)
over4years
IT-hu14.18-IL2 With Radiation, Nivolumab and Ipilimumab for Melanoma (clinicaltrials.gov)
P1/2, N=61, Recruiting, University of Wisconsin, Madison | Suspended --> Recruiting
Clinical • Enrollment open
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IL2RA (Interleukin 2 receptor, alpha) • IL2 (Interleukin 2)
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Opdivo (nivolumab) • Yervoy (ipilimumab) • lorukafusp alfa (APN301)
over4years
Outcome-related signatures identified by Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated After Starting Hu14.18-IL2. (PubMed, Clin Cancer Res)
We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNAseq analyses detected shortly after initiation of hu14.18-IL2 therapy are associated with long term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy.
Journal
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IL2 (Interleukin 2)
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TILs
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lorukafusp alfa (APN301)