Novel Combinations of Human Immunomodulatory mAbs Lacking Cardiotoxic Effects for Therapy of TNBC
Cinzia Vetrei1,2, Margherita Passariello1,2, Guendalina Froechlich1,3
1Ceinge-Biotecnologie Avanzate s.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy.
Abstract:
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by a higher mortality rate among breast cancer subtypes. Poly(ADP-ribose) polymerase (PARP) inhibitors are used in clinics to treat a subgroup of TNBC patients, but other targeted therapies are urgently needed. Programmed death-ligand 1 (PD-L1), involved in tumor immune escape, was recently identified as a target for TNBC; accordingly, the anti-PD-L1 monoclonal antibody (mAb), atezolizumab, has been approved by FDA in combination with Paclitaxel for the therapy of metastatic TNBC. Here, we tested novel combinations of fully human immunomodulatory mAbs, including anti-PD-L1 mAbs generated in our laboratory and atezolizumab, on TNBC and other tumor cell lines. We evaluated their anti-tumor efficacy when used as single agents or in combinatorial treatments with anti-CTLA-4 mAbs in in vitro co-cultures of hPBMCs with tumor cells, by measuring tumor cell lysis and IL-2 and IFNγ cytokines secretion by lymphocytes. In parallel, by using co-cultures of hPBMCs and cardiomyocytes, we analyzed the potential cardiotoxic adverse side effects of the same antibody treatments by measuring the cardiac cell lysis and the secretion of pro-inflammatory cytokines. We identified novel combinations of immunomodulatory mAbs endowed with more potent anti-cancer activity on TNBC and lower cardiotoxic side effects than the combination of atezolizumab and ipilimumab.
Insights
Novel immunotherapy combinations show potent anti-cancer activity against triple-negative breast cancer (TNBC) with reduced cardiotoxicity. These findings offer new therapeutic strategies for TNBC, improving patient outcomes and safety.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies.
- Current treatments include PARP inhibitors and anti-PD-L1 monoclonal antibodies (mAbs) like atezolizumab, but novel approaches are needed.
- Tumor immune escape via PD-L1 and CTLA-4 pathways presents therapeutic targets.
Purpose of the Study:
- To evaluate novel combinations of immunomodulatory mAbs, including in-house anti-PD-L1 mAbs and atezolizumab, for TNBC treatment.
- To assess the anti-tumor efficacy of these combinations in vitro.
- To analyze potential cardiotoxic side effects of these antibody treatments.
Main Methods:
- In vitro co-culture systems using human peripheral blood mononuclear cells (hPBMCs) with TNBC and other tumor cell lines.
- Measurement of tumor cell lysis and cytokine secretion (IL-2, IFNγ) by lymphocytes.
- Co-culture of hPBMCs with cardiomyocytes to assess cardiotoxicity via cell lysis and cytokine release.
Main Results:
- Identified novel immunomodulatory mAb combinations with enhanced anti-cancer activity against TNBC.
- These novel combinations demonstrated greater potency compared to atezolizumab and ipilimumab.
- The identified combinations exhibited reduced cardiotoxic adverse effects.
Conclusions:
- Novel combinations of immunomodulatory mAbs show promise for TNBC therapy.
- These combinations offer improved anti-tumor efficacy and a better safety profile regarding cardiotoxicity.
- Further research into these mAb combinations could lead to improved treatment strategies for TNBC.
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