323TiP Updated study design of mRNA-4359-P101: Cohort expansions in first-line and CPI-R/R melanoma and PD-L1-high first-line NSCLC

G. Middleton; A. Khattak; D.J. Pinato; A. Jimeno; M.R. Middleton; G. Long; R.J. Sullivan; A. Rohatgi; M. Gutierrez; D. Sarker; R. Sweis; S. Parakh; I. Karydis; A. Daud; J.E. Bauman; A.M. Weise; A.M. Leighton-Swayze; F. Barlaskar; S. Pascarella; P. Spiliopoulou

doi:10.1016/j.iotech.2025.101522

Abstract

Background
Despite major advancements with immune checkpoint inhibitors (CPIs), many patients’ disease does not respond or ultimately relapses, underscoring the need for novel approaches. mRNA-4359 is an intramuscular mRNA-based cancer antigen therapy that encodes programmed death-ligand 1 and indoleamine 2,3-dioxygenase 1 (PD-L1/IDO1) peptides to stimulate antigen-specific T cells. These T cells are intended to target cancer and immunosuppressive cells to promote an immune-permissive tumor microenvironment. mRNA-4359 is being evaluated in combination with CPIs to potentially enhance anti-tumor activity.

Trial Design
mRNA-4359-P101 (NCT05533697) is an ongoing, phase I/II, open-label, first-in-human, non-randomized study evaluating mRNA-4359 alone or in combination with CPIs. Following completion of dose-escalation and dose-optimization, Protocol Amendment 3.0 (published 28 July 2025) added and/or expanded upon cohorts in melanoma and non-small cell lung cancer (NSCLC). Primary and secondary objectives include safety, tolerability, anti-tumor activity, and T cell profile changes. Expansion cohorts are: (Arm 2b) first-line advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and EGFR/ALK-negative (n=50); (Arm 2c) first-line advanced melanoma treated with ipilimumab/nivolumab (n=45); (Arms 1b and 2d) ≥ second-line CPI-resistant/refractory (CPI-R/R) melanoma with PD-L1 TPS ≥1% (combined planned n=97). Patients receive intramuscular mRNA-4359 with intravenous pembrolizumab in Arms 1b, 2b, and 2d, and with ipilimumab/nivolumab in Arm 2c. Enrollment is now ongoing in these expansion cohorts.

Clinical trial identification
NCT05533697.

Original language	English
Article number	101522
Pages (from-to)	32-33
Number of pages	2
Journal	Immuno-Oncology and Technology
Volume	28
Issue number	S
DOIs	https://doi.org/10.1016/j.iotech.2025.101522
Publication status	Published - 26 Dec 2025
Event	ESMO Immuno-Oncology Congress 2025 - Queen Elizabeth II Centre, London, United Kingdom Duration: 10 Dec 2025 → 12 Dec 2025 https://www.esmo.org/meeting-calendar/esmo-immuno-oncology-congress-2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Middleton, G., Khattak, A., Pinato, D. J., Jimeno, A., Middleton, M. R., Long, G., Sullivan, R. J., Rohatgi, A., Gutierrez, M., Sarker, D., Sweis, R., Parakh, S., Karydis, I., Daud, A., Bauman, J. E., Weise, A. M., Leighton-Swayze, A. M., Barlaskar, F., Pascarella, S., & Spiliopoulou, P. (2025). 323TiP Updated study design of mRNA-4359-P101: Cohort expansions in first-line and CPI-R/R melanoma and PD-L1-high first-line NSCLC. Immuno-Oncology and Technology, 28(S), 32-33. Article 101522. https://doi.org/10.1016/j.iotech.2025.101522

@article{7d1eaf2824a14338b5398baa3de40255,

title = "323TiP Updated study design of mRNA-4359-P101: Cohort expansions in first-line and CPI-R/R melanoma and PD-L1-high first-line NSCLC",

abstract = "Background Despite major advancements with immune checkpoint inhibitors (CPIs), many patients{\textquoteright} disease does not respond or ultimately relapses, underscoring the need for novel approaches. mRNA-4359 is an intramuscular mRNA-based cancer antigen therapy that encodes programmed death-ligand 1 and indoleamine 2,3-dioxygenase 1 (PD-L1/IDO1) peptides to stimulate antigen-specific T cells. These T cells are intended to target cancer and immunosuppressive cells to promote an immune-permissive tumor microenvironment. mRNA-4359 is being evaluated in combination with CPIs to potentially enhance anti-tumor activity. Trial Design mRNA-4359-P101 (NCT05533697) is an ongoing, phase I/II, open-label, first-in-human, non-randomized study evaluating mRNA-4359 alone or in combination with CPIs. Following completion of dose-escalation and dose-optimization, Protocol Amendment 3.0 (published 28 July 2025) added and/or expanded upon cohorts in melanoma and non-small cell lung cancer (NSCLC). Primary and secondary objectives include safety, tolerability, anti-tumor activity, and T cell profile changes. Expansion cohorts are: (Arm 2b) first-line advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50\% and EGFR/ALK-negative (n=50); (Arm 2c) first-line advanced melanoma treated with ipilimumab/nivolumab (n=45); (Arms 1b and 2d) ≥ second-line CPI-resistant/refractory (CPI-R/R) melanoma with PD-L1 TPS ≥1\% (combined planned n=97). Patients receive intramuscular mRNA-4359 with intravenous pembrolizumab in Arms 1b, 2b, and 2d, and with ipilimumab/nivolumab in Arm 2c. Enrollment is now ongoing in these expansion cohorts. Clinical trial identification NCT05533697.",

author = "G. Middleton and A. Khattak and D.J. Pinato and A. Jimeno and M.R. Middleton and G. Long and R.J. Sullivan and A. Rohatgi and M. Gutierrez and D. Sarker and R. Sweis and S. Parakh and I. Karydis and A. Daud and J.E. Bauman and A.M. Weise and A.M. Leighton-Swayze and F. Barlaskar and S. Pascarella and P. Spiliopoulou",

year = "2025",

month = dec,

day = "26",

doi = "10.1016/j.iotech.2025.101522",

language = "English",

volume = "28",

pages = "32--33",

journal = "Immuno-Oncology and Technology",

issn = "2590-0188",

publisher = "Elsevier",

number = "S",

note = "ESMO Immuno-Oncology Congress 2025 ; Conference date: 10-12-2025 Through 12-12-2025",

url = "https://www.esmo.org/meeting-calendar/esmo-immuno-oncology-congress-2025",

}

Middleton, G, Khattak, A, Pinato, DJ, Jimeno, A, Middleton, MR, Long, G, Sullivan, RJ, Rohatgi, A, Gutierrez, M, Sarker, D, Sweis, R, Parakh, S, Karydis, I, Daud, A, Bauman, JE, Weise, AM, Leighton-Swayze, AM, Barlaskar, F, Pascarella, S & Spiliopoulou, P 2025, '323TiP Updated study design of mRNA-4359-P101: Cohort expansions in first-line and CPI-R/R melanoma and PD-L1-high first-line NSCLC', Immuno-Oncology and Technology, vol. 28, no. S, 101522, pp. 32-33. https://doi.org/10.1016/j.iotech.2025.101522

TY - JOUR

T1 - 323TiP Updated study design of mRNA-4359-P101

T2 - ESMO Immuno-Oncology Congress 2025

AU - Middleton, G.

AU - Khattak, A.

AU - Pinato, D.J.

AU - Jimeno, A.

AU - Middleton, M.R.

AU - Long, G.

AU - Sullivan, R.J.

AU - Rohatgi, A.

AU - Gutierrez, M.

AU - Sarker, D.

AU - Sweis, R.

AU - Parakh, S.

AU - Karydis, I.

AU - Daud, A.

AU - Bauman, J.E.

AU - Weise, A.M.

AU - Leighton-Swayze, A.M.

AU - Barlaskar, F.

AU - Pascarella, S.

AU - Spiliopoulou, P.

PY - 2025/12/26

Y1 - 2025/12/26

N2 - Background Despite major advancements with immune checkpoint inhibitors (CPIs), many patients’ disease does not respond or ultimately relapses, underscoring the need for novel approaches. mRNA-4359 is an intramuscular mRNA-based cancer antigen therapy that encodes programmed death-ligand 1 and indoleamine 2,3-dioxygenase 1 (PD-L1/IDO1) peptides to stimulate antigen-specific T cells. These T cells are intended to target cancer and immunosuppressive cells to promote an immune-permissive tumor microenvironment. mRNA-4359 is being evaluated in combination with CPIs to potentially enhance anti-tumor activity. Trial Design mRNA-4359-P101 (NCT05533697) is an ongoing, phase I/II, open-label, first-in-human, non-randomized study evaluating mRNA-4359 alone or in combination with CPIs. Following completion of dose-escalation and dose-optimization, Protocol Amendment 3.0 (published 28 July 2025) added and/or expanded upon cohorts in melanoma and non-small cell lung cancer (NSCLC). Primary and secondary objectives include safety, tolerability, anti-tumor activity, and T cell profile changes. Expansion cohorts are: (Arm 2b) first-line advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and EGFR/ALK-negative (n=50); (Arm 2c) first-line advanced melanoma treated with ipilimumab/nivolumab (n=45); (Arms 1b and 2d) ≥ second-line CPI-resistant/refractory (CPI-R/R) melanoma with PD-L1 TPS ≥1% (combined planned n=97). Patients receive intramuscular mRNA-4359 with intravenous pembrolizumab in Arms 1b, 2b, and 2d, and with ipilimumab/nivolumab in Arm 2c. Enrollment is now ongoing in these expansion cohorts. Clinical trial identification NCT05533697.

AB - Background Despite major advancements with immune checkpoint inhibitors (CPIs), many patients’ disease does not respond or ultimately relapses, underscoring the need for novel approaches. mRNA-4359 is an intramuscular mRNA-based cancer antigen therapy that encodes programmed death-ligand 1 and indoleamine 2,3-dioxygenase 1 (PD-L1/IDO1) peptides to stimulate antigen-specific T cells. These T cells are intended to target cancer and immunosuppressive cells to promote an immune-permissive tumor microenvironment. mRNA-4359 is being evaluated in combination with CPIs to potentially enhance anti-tumor activity. Trial Design mRNA-4359-P101 (NCT05533697) is an ongoing, phase I/II, open-label, first-in-human, non-randomized study evaluating mRNA-4359 alone or in combination with CPIs. Following completion of dose-escalation and dose-optimization, Protocol Amendment 3.0 (published 28 July 2025) added and/or expanded upon cohorts in melanoma and non-small cell lung cancer (NSCLC). Primary and secondary objectives include safety, tolerability, anti-tumor activity, and T cell profile changes. Expansion cohorts are: (Arm 2b) first-line advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and EGFR/ALK-negative (n=50); (Arm 2c) first-line advanced melanoma treated with ipilimumab/nivolumab (n=45); (Arms 1b and 2d) ≥ second-line CPI-resistant/refractory (CPI-R/R) melanoma with PD-L1 TPS ≥1% (combined planned n=97). Patients receive intramuscular mRNA-4359 with intravenous pembrolizumab in Arms 1b, 2b, and 2d, and with ipilimumab/nivolumab in Arm 2c. Enrollment is now ongoing in these expansion cohorts. Clinical trial identification NCT05533697.

U2 - 10.1016/j.iotech.2025.101522

DO - 10.1016/j.iotech.2025.101522

M3 - Abstract

SN - 2590-0188

VL - 28

SP - 32

EP - 33

JO - Immuno-Oncology and Technology

JF - Immuno-Oncology and Technology

IS - S

M1 - 101522

Y2 - 10 December 2025 through 12 December 2025

ER -

323TiP Updated study design of mRNA-4359-P101: Cohort expansions in first-line and CPI-R/R melanoma and PD-L1-high first-line NSCLC

Abstract

UN SDGs

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