Selected Articles from This Issue

The selective expression of CLDN18.2 in gastric and pancreas cancers represents an opportunity to use this cell surface antigen to develop novel antibody-based therapeutics for these hard-to-treat cancers. Here, O'Brien and colleagues describe the development of a high affinity CLDN18.2 selective monoclonal antibody (CLDN18.2-307-mAb) and antibody drug conjugate (CLDN18.2-307-ADC). CLDN18.2-307-mAb shows efficacy in CLDN18.2 positive cancer cell line xenografts through induction of antibody dependent cell mediated cytotoxicity (ADCC). Sustained tumor regressions were observed in response to treatment with CLDN18.2-307-ADC in patient derived xenografts expressing as few as 15% CLDN18.2 positive cells. Both molecules are now in phase 1 clinical development.

Efforts to improve outcomes for cancer patients treated with radiation therapy include combinations with immunotherapy. After tumor radiation, the initial antitumor response of M1 macrophages polarizes into tumor-promoting M2 macrophages, underlying cancer relapse and metastasis. Therefore, strategies regulating tumor macrophages post-radiation can enhance the therapeutic effectiveness of radiation therapy. Here, we report intratumor adaptive cell therapy using HDAC6 inhibitor (SP-2-225) treated M1 macrophages. The combination of conditioned M1 macrophages with an irradiated tumor microenvironment increased the M1/M2 ratio and infiltration of CD8 T-cells. Our findings demonstrate the ability of HDAC6 inhibitors to regulate macrophage function and phenotype as a cell therapy for use in combination with radiation therapy.

Malignant peripheral nerve sheath tumor (MPNST) is the most common cause of death in young people with neurofibromatosis type I (NF1). Lemberg and colleagues previously showed that the glutamine amidotransferase (GA) inhibitor JHU395 partially impeded tumor growth in models of MPNST with a prominent effect on inhibiting de novo purine synthesis. In this issue they report the discovery of Pro-905, a novel and well-tolerated protide targeting purine salvage. They show that when Pro-905 is combined with JHU395, robust antitumor efficacy is observed. This approach should be further explored in other NF1 mutant or RAS-ERK active tumors.

Antibody-drug conjugates (ADCs) are cancer therapeutics that aim to combine antigen selectivity with potent cytotoxicity in a single molecule. Integrin beta-6 (IB6) may hold promise as a cancer target due to its expression profile across multiple cancers. Here, Lyon and colleagues characterize the promising preclinical antitumor activity of the IB6-directed vedotin ADC SGN-B6A. They demonstrate IB6-dependent activity of SGN-B6A in cell line models and in a panel of NSCLC patient-derived xenografts. They also disclose safety findings from a study in cynomolgus monkeys. Together, these results suggest IB6 is a promising cancer target and provide the basis for current clinical investigation of SGN-B6A.