TGFβi Natural Killer (NK) cells in Advanced GD2-expressing Breast Cancers (DiG NKs): A novel combination therapy to tackle metastatic TNBC — ASN Events
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TGFβi Natural Killer (NK) cells in Advanced GD2-expressing Breast Cancers (DiG NKs): A novel combination therapy to tackle metastatic TNBC (#167)

Marcelo Pereira 1 , Sumithira Vasu 2 , Lynn O’Donnell 2 , Marcos DeLima 2 , Zihai Li 3 , Daniel Stover 3 , Robert Wesolowski 4 , Sagar Sardesai 4 , Gilbert Bader 4 , Mathew Cherian 4 , Kai Johnson 4 , Ashley Pariser 4 , Dionisa Quiroga 2 , Nicole Williams 4 , Joanne Kim 3 , Dean Lee 1 , Margaret E Gatti-Mays 3
  1. Center for Childhood Cancer, Abigail Wexner Research Institute at Nationwide Children's Hospital , Columbus, Ohio, USA
  2. The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
  3. Pelotonia Institute for Immuno-Oncology, Division of Medical Oncology, Department of Internal Medicine, The Ohio State University , Columbus, Ohio, USA
  4. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA

Breast cancer (BC) is often immunologically cold, characterized by low mutational burden and low PD-L1 expression. This intrinsic resistance to immunotherapy is due to low neoantigen levels, defective antigen presentation, and immunosuppressive signals like TGF-β in the tumor microenvironment (TME), which exclude effector T cells and NK cells. These factors impede effective anti-tumor immune responses, as reflected by modest results with immune checkpoint inhibitor (ICI) monotherapy in BC. Although neoantigens are rare, surface expression of the tumor-associated disialoganglioside GD2 is high in aggressive BC subtypes, providing strong rationale for evaluating an anti-GD2 antibody with NK cells in BC.

Therefor, we generated pre-clinical data that support a clinical trial to evaluate the stepwise addition of gemcitabine (for TME modulation), TGFβ-imprinted, IL-21-expanded allogenic universal donor NK cells (TGFβi NKs, having tissue homing and TGFβ-resistance), and naxitamab (an FDA-approved anti-GD2 monoclonal antibody) to overcome these intrinsic resistance mechanisms in BC.

Our preclinical data shows that TGFβi NK cells had improved binding avidity to breast cancer cell lines and that anti-GD2 treatment increased ADCC-mediated cell lysis by TGFβi NKs. Gemcitabine treatment did not alter GD2 expression on MDA-MB231 tumor cells but induced MICA expression. In vivo, female NSG mice injected with MDA-MB231 cells were divided into four groups: Tumor only controls, Gem alone, TGFβi NK + aGD2 (NK-GD2), and Gem + TGFβi NK + aGD2 (DigNK). The DigNK group showed superior weight stability and tumor growth reduction compared to other groups. Improved survival was observed in NK-GD2 and DigNK arms, with no significant toxicities.

Our preclinical data supported a Phase 1b/2 clinical trial to evaluate this immunotherapy combination in patients with aggressive, immunotherapy-resistant metastatic BC, which is now open and enrolling at The Ohio State University Comprehensive Cancer Center (NCT06026657, Columbus, OH). We plan to recruit up to 39 evaluable patients.