NL-201

The immune stimulatory mechanisms triggered by NL-201 and RT resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic cancers. Our results support further preclinical and clinical investigation of this novel synergism regimen in locally advanced and metastatic settings.

The NL-201 enhancement of cytotoxicity by CD8+ T cells and NK cells supports additional exploration aimed at optimizing combinatorial approaches. These findings will inform the design of planned clinical studies with NL-201 in patients with B-cell lymphomas and other hematological malignancies.

Additional in vitro and in vivo NHL models are being tested to enhance understanding of the interaction between NL-201 and other approved therapies within the hematopoietic tumor microenvironment. These data will be used to design future clinical trials of NL-201 in novel regimens to treat hematological malignancies.

The demonstration that NL-201 can convert 'cold' tumors to immunologically 'hot' tumors may provide a novel therapeutic option for patients unresponsive to current standard of care checkpoint inhibitors. A Phase 1 study of NL-201 in patients with advanced solid tumors is currently underway (NCT04659629).

Rechallenged animals failed to develop tumors, demonstrating durable tumor-specific immunity after IT NL-201 treatment. Results of this study support planned clinical investigation of IT NL-201 administration to increase NL-201 concentrations in accessible lesions.

We then used the VHH-peptide platform to evaluate a panel of candidate neoantigens in vivo in a mouse model of pancreatic cancer. None of the candidate neoantigens tested led to protection from tumour challenge; however, we were able to show vaccine-induced CD8 T cell responses to a melanoma self-antigen that was augmented by combination therapy with the synthetic cytokine mimetic Neo2/15.

The synergy of NL-201 with TA99 may result from enhanced NK-mediated antibody-dependent cellular cytotoxicity (ADCC), while the synergy with CPIs may result from CD8+ T cell stimulation, which can turn ‘cold’ tumor microenvironments ‘hot’. Conclusions The broad activity of NL-201 across diverse tumor models and its potential to be combined with a variety of established and exploratory cancer immunotherapies to achieve synergistic antitumor activity highlights the opportunity for NL-201 to become a critical component of future immunotherapy regimens.

The synergy of NL-201 with TA99 may result from enhanced NK-mediated antibody-dependent cellular cytotoxicity (ADCC), while the synergy with CPIs may result from CD8+ T cell stimulation, which can turn ‘cold’ tumor microenvironments ‘hot’. Conclusions The broad activity of NL-201 across diverse tumor models and its potential to be combined with a variety of established and exploratory cancer immunotherapies to achieve synergistic antitumor activity highlights the opportunity for NL-201 to become a critical component of future immunotherapy regimens.

In a B cell tumor xenograft model, targeted Neo-2/15 effectively increased CAR-T cell expansion and prolonged survival compared to treatment with CAR-T cells and non-targeted Neo-2/15. Together, these results show that engineered versions of Neo-2/15 induce robust expansion of CAR-T cells and can enhance their antitumor activity.