MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial

Abstract

BackgroundImmunotherapy offers a promising novel approach for the treatment of cancer and both adoptive T-cell transfer and immune modulation lead to regression of advanced melanoma. However, the potential synergy between these two strategies remains unclear.MethodsWe investigated in 12 patients with advanced stage IV melanoma the effect of multiple MART-1 analog peptide vaccinations with (n = 6) or without (n = 6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs at day (D) 0 (Trial registration No: NCT00324623). All patients were selected on the basis of ex vivo detectable MART-1-specific CD8 T-cell responses and immunized at D0, 8, 15, 22, 28, 52, and 74 post-reinfusion.ResultsAfter immunization, a significant expansion of MART-1-specific CD8 T cells was measured in 83% (n = 5/6) and 17% (n = 1/6) of patients from the IMP321 and control groups, respectively (P < 0.02). Compared to the control group, the mean fold increase of MART-1-specific CD8 T cells in the IMP321 group was respectively >2-, >4- and >6-fold higher at D15, D30 and D60 (P < 0.02). Long-lasting MART-1-specific CD8 T-cell responses were significantly associated with IMP321 (P < 0.02). At the peak of the response, MART-1-specific CD8 T cells contained higher proportions of effector (CCR7− CD45RA+/−) cells in the IMP321 group (P < 0.02) and showed no sign of exhaustion (i.e. were mostly PD1−CD160−TIM3−LAG3−2B4+/−). Moreover, IMP321 was associated with a significantly reduced expansion of regulatory T cells (P < 0.04); consistently, we observed a negative correlation between the relative expansion of MART-1-specific CD8 T cells and of regulatory T cells. Finally, although there were no confirmed responses as per RECIST criteria, a transient, 30-day partial response was observed in a patient from the IMP321 group.ConclusionsVaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs induced more robust and durable cellular antitumor immune responses, supporting further development of IMP321 as an adjuvant for future immunotherapeutic strategies.

Clinical blockade of PD1 and LAG3 — potential mechanisms of action

“…IMP321 consists of the four extracellular immunoglobulin-like domains of LAG3 fused to the Fc portion of human IgG1. In these trials, IMP321 was assessed in combination with antiviral vaccines or in combination with chemotherapy or other immune therapies for cancer [116][117][118][119] . Although there is no known role for sLAG3 in directly inhibiting T cells, it is possible that sLAG3 affects the interaction of membrane LAG3 with MHC class II molecules and thus indirectly affects T cell function.…”

The role of active vaccination in cancer immunotherapy: lessons from clinical trials

“…In this trial, an antibody, IMP321, was given to patients to block LAG-3 in combination with a melanoma vaccine targeting MART-1. Five out of six patients had an increase in the MART-1 specific T-cells when given the vaccine in combination with LAG-3 inhibition, while only one of six patients had an increased T-cell response to the vaccine alone [62]. TIM3 is another molecule that contributes to CD8 T-cells exhaustion discovered in HIV patients, and blockade of TIM3 was found to restore the functionality of exhausted CD8 T-cells isolated from HCV patients [63,64].…”

Combination Strategies to Enhance the Potency of Monocyte-Derived Dendritic Cell-Based Cancer Vaccines

“…Among CD8 + TIL, LAG-3 is commonly co-expressed with PD-1 [21], prompting the performance of a Phase I trial examining the clinical/immunologic benefits of treating cancer patients with antagonist LAG-3 monoclonal antibody alone or in combination with anti-PD-1-based immunotherapy (NCT01968109). A LAG-3-Ig fusion protein that targets the natural ligand of LAG-3 (i.e., MHC-II), is also currently being evaluated as an adjuvant within the context of a Phase I MART-1 peptide-based vaccine trial (NCT00324623), where the combination vaccine has shown the ability to induce higher levels of more durable MART-1-specific CD8+ T cells, while coordinately decreasing Treg frequencies in the peripheral blood of treated patients [22]. The implementation of these new checkpoint inhibitors as single modalities and in combination with alternate forms of immunotherapy, including DC-based vaccines holds great current/future promise in the clinical management of cancer patients.…”