Enhanced CD8+ T-cell infiltration, PD-L1 expression, and T-cell repertoire expansion in patients with metastatic uveal melanoma responding to treatment with RP2 alone or in combination with nivolumab
Praveen K. Bommareddy1, Alireza Kalbasi1, Kevin J. Harrington2, Anna Olsson-Brown3, Tze Y. Chan3, Pablo Nenclares2, Isla Leslie2, Mark R. Middleton4, Aglaia Skolariki4, David M. Cohan1, Konstantinos Xynos1, Robert Coffin1, Joseph J. Sacco3
1Replimune, Inc., Woburn, MA, USA; 2The Institute of Cancer Research, London, UK; 3The Clatterbridge Cancer Centre, Wirral, UK and University of Liverpool, Liverpool, UK; 4Churchill Hospital and University of Oxford, Oxford, UK
Background
- RP2 is a genetically modified herpes simplex virus type 1 that encodes granulocyte- macrophage colony-stimulating factor, the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R-), and a human anti-CTLA-4antibody-like molecule1
- RP2 ± nivolumab is currently being tested in clinical trials in a range of solid tumors including in patients with metastatic uveal melanoma (mUM)
- Uveal melanoma is the most common form of intraocular primary malignancy and accounts for ~90% of all cases of ocular melanoma and up to 5% of all melanomas2-5
- Approximately 50% of patients with uveal melanoma will develop distant metastases, with the liver representing the most frequent site of metastatic disease (~90%). Following metastasis, median overall survival is <1 year2,3
- As of November 20, 2023, 17 patients with uveal melanoma were enrolled (RP2 monotherapy, n = 3; RP2 + nivolumab, n = 14)
- Here, we present the biomarker data from patients with mUM treated with RP2 in combination with nivolumab
Patient demographics and baseline characteristics
RP2 monotherapy (n = 3) | RP2 + nivolumab (n = 14) | ||
Age, median (range), years | 55 (48-64) | 65 (38-82) | |
Sex, n (%) | |||
Female | 0 | 5 | (35.7) |
Male | 3 (100.0) | 9 | (64.3) |
ECOG PS, n (%) | |||
0 | 3 (100.0) | 11 (78.6) | |
1 | 0 | 3 (21.4) | |
Prior lines of treatment, n (%) | |||
0 | 0 | 2 (14.3) | |
1 | 1 (33.3) | 5 | (35.7) |
2 | 1 (33.3) | 5 | (35.7) |
3 | 0 | 1 | (7.1) |
4 | 1 (33.3) | 1 | (7.1) |
Prior therapies, n (%) | 3 (100.0) | 10 | (71.4) |
Anti-PD-1a | |||
Anti-CTLA-4b | 3 (100.0) | 10 | (71.4) |
Anti-PD-1 and anti-CTLA-4 | 3 (100.0) | 9 (64.3) |
aAlone or combined with anti-CTLA-4.bAlone or combined with anti-PD-1.
CTLA-4, cytotoxic T-lymphocyte antigen 4; ECOG PS, Eastern Cooperative Oncology Group performance status; PD-1, programmed cell death protein 1.
Increase in CD8+ T cells influx and PD-L1 expression are observed in patients
treated with RP2 combined with nivolumab
RP2 ± nivolumab in patients who progressed on prior immunotherapy
201-4402-0014 PR | 201-4401-0003 PR |
RP2 + nivolumab combination | RP2 monotherapy |
More than 50% tumor reduction was observed | Extensive liver metastases |
Prior therapies: ipilimumab, pembrolizumab | Prior therapies: ipilimumab + nivolumab |
Patient progressed at 21.5 months after | Patient progressed at 14.3 months after |
initiating treatment with RP2 | initiating treatment with RP2 |
Responses were observed in both HLA-A2*02:01-positive and HLA-A2*02:01-
negative patients
RP2 - A fusion-enhanced oncolytic HSV expressing anti-CTLA-4
αCTLA-4,anti-cytotoxicT-lymphocyte antigen 4; GALV-GP-R−, gibbon ape leukemia virus glycoprotein with the R sequence deleted; hGM-CSF, human granulocyte- macrophage colony-stimulating factor; HSV, herpes simplex virus; ICP, infected cell protein; P, promoter; pA, polyA signal; US11, unique short 11; X, denotes inactivation of viral protein.
Objectives
To evaluate the efficacy of RP2 alone and in combination with nivolumab and the impact |
on tumor biopsies and peripheral blood mononuclear cell (PBMC) samples collected from |
Screening
Day 43
Screening
201-3412-0001 PR | 201-4402-0014 PR | |||||||
CD8 | PD-L1 | CD8 | PD-L1 | |||||
Screening | ||||||||
Day 43
201-4401-0021 SD | 201-4403-0015 SD | ||||||
CD8 | PD-L1 | CD8 | PD-L1 | ||||
Screening |
- IHC of the day 43 biopsy demonstrates an increase in intratumoral CD8 T-cell infiltration and PD-L1 expression in patients achieving partial response (PR) and stable disease (SD)
HLA-A*02:01 | Positive | Negative | Total |
status | (n = 6) | (n = 11) | (n = 17) |
PR | 1 (16.7%) | 4 (36.4%) | 5 (29.4%) |
SD | 2 (33.3%) | 3 (27.3%) | 5 (29.4%) |
PD/NE | 3 (50.0%) | 4 (36.4%) | 7 (41.2%) |
TCR sequencing of PBMCs demonstrated expansion of existing T cell clones
along with the generation of new tumor-specific T cell clones
mUM patients enrolled in the NCT04336241 clinical trial |
Methods
Day 43
Day 43
201-3412-0001 PR
201-4401-0021 SD | 201-4402-0007 PR | 201-4402-0014 PR | 201-4403-0018 SD |
MART-1 clone
Part 1
Dose | RP2D | (28 days) |
escalation | selected | Screening |
- The RP2D was identified as
1 × 106 PFU/mL once, followed by up to 7 doses of 1 × 107 PFU/mL per dosing day - Re-initiationof up to 8 additional RP2 doses is permitted if prespecified criteria are met
Part 2 | |
Cohort 2a (completed) | Cohort 2b |
Combination treatment (N = 30) | Expansion cohort (N = 30) |
All-comers solid tumors | Specified solid tumors |
RP2 (Q2W × 8 doses) + nivo (240 mg | RP2 (Q2W × 4 doses) followed by RP2 (Q4W × 4 doses) up to 8 |
Q2W × 4 mo; 480 mg Q4W × 20 mo) | doses + nivo starting at week 6 (240 mg Q2W or 480 mg Q4W × |
22 mo) | |
Part 3 | |
RP2 monotherapy (N = 15) | |
Specified solid tumors | |
RP2 (Q2W × 4 doses) followed by RP2 (Q4W × 4 | |
doses) up to 8 doses |
Treatment period (24 mo)
Overall survival (up to 3 y from C1D1)
RP2 is administered via direct intratumoral injection into superficial/subcutaneous lesions or into deep/visceral lesions using image guidance (eg, ultrasound or CT)
EOT + safety follow-up
Screening
Day 43
201-4403-0014 PD | 201-4402-0019 PD | 201-4401-0002 PD | |||||||||||
CD8 | PD-L1 | CD8 | PD-L1 | CD8 | PD-L1 | ||||||||
Screening | Screening | ||||||||||||
Day 43 | Day 43 | ||||||||||||
Duration of benefit; objective response rate and disease control rate
Day 43
Day 1
TCR sequencing of PBMCs demonstrated expansion of pre-existing and generation of new T cell |
clones following treatment with RP2 with nivolumab |
Numerous clones that exhibited expansion were first identified on day 43, suggesting that the |
treatment contributed not only to the proliferation of pre-existing T cell clones but also to the de novo |
generation of new T cell clones |
The expansion of new or pre-existing clones in the peripheral blood did not show correlation with |
clinical response |
C1D1, cycle 1 day 1; CT, computed tomography; EOT, end of treatment; nivo, nivolumab; PFU, plaque-forming unit; RP2D, recommended phase 2 dose; Q2W, every 2 weeks; Q4W, every 4 weeks.
RP2 ± nivolumab
Screening | Day 1 | Day 15 | Day 43 |
In this pretreated population, the ORR was 29.4% (5/17; all PRs; RP2 monotherapy, 1/3; RP2 + nivolumab, 4/17)
RP2 monotherapy
Summary and conclusions
Biomarker analysis shows that RP2 treatment in combination with nivolumab leads to significant immune |
Archival/fresh biopsy
Peripheral blood mononuclear cells
Tumor biopsies and PBMCs were collected at screening and at day 43 |
Tumor immune microenvironment was analyzed by immunohistochemistry (IHC) to detect |
RP2 monotherapy
The disease control rate (complete response + PR + SD) was 58.8% (10/17; 5 patients with SD in RP2 + nivolumab cohort)
The median (range) duration of response at
activation. This is evidenced by the expansion of pre-existing T cell clones and the emergence of new T cell |
clones in the peripheral blood, as well as increased PD-L1 expression and enhanced CD8+ T-cell infiltration in |
tumors form mUM patients achieving PR and SD |
RP2 monotherapy and RP2 + nivolumab demonstrate a meaningful antitumor activity with durable responses in |
patients with mUM, including in patients with liver metastases. These responses were observed in both HLA- |
|
CD8 (SP57 clone, Ventana) and PD-L1(PD-L1 IHC 28-8 pharmDx by Agilent) |
Systemic antitumor immunity was assessed using PBMCs by sequencing the CDR3 |
regions of human TCRβ chains using the immunoSEQ assay. |
RP2 monotherapythe data cutoff was 11.47 (2.78-21.22) months
Duration on study (days)
A2*02:01-positive and HLA-A2*02:01-negative patients |
Based on data in this population, planning is underway for a potentially registrational clinical trial with RP2 |
in advanced uveal melanoma |
Acknowledgements: | References: | 2. | Jager MJ, et al. Nat Rev Dis Primers. 2020;6(1):24. | 4. Mahendraraj K, et al. Clin Ophthalmol. 2017;11:153-60. | Study Sponsor: |
The authors would like to thank the patients for their participation in the trial. The authors would also like to acknowledge the contributions of Moran Mishal, | 1. Thomas S, et al. J Immunother Cancer. 2019;7(1):214. | 3. | National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN | ||
5. Branisteanu DC, et al. Exp Ther Med. 2021;22(6):1428. | The study is sponsored by Replimune Inc., Woburn, MA, USA. | ||||
Vineetha Edavana, and Mary Kate Cronin. | Guidelines®). Melanoma: Uveal. Version 2.2022. | ||||
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Replimune Group Inc. published this content on 01 April 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 08 April 2024 16:29:04 UTC.