Peter Kar Han Lau

Adoptive cellular therapies (ACT), including tumour‐infiltrating lymphocyte (TIL), T‐cell receptor‐engineered T (TCR‐T) cell and chimeric antigen receptor T‐cell (CAR‐T) therapies, represent an evolving class of immunotherapies with established efficacy in selected haematological malignancies and emerging applications in solid tumours. Additional platforms under investigation include virus‐specific T cells, tumour‐associated antigen‐specific T cells, natural killer (NK) cell therapies and dendritic cell‐based therapies. The therapeutic scope of ACT is expanding beyond oncology into autoimmune and fibrotic diseases, infectious diseases and inherited metabolic and immune disorders, highlighting the broad potential of cellular immunotherapy platforms. In solid tumours, efficacy remains limited by tumour antigen heterogeneity, immunosuppressive tumour micro‐environment and impaired immune cell trafficking and persistence. These barriers are driving development of next‐generation cellular products and combination strategies. Characteristic immune‐mediated toxicities, particularly cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS), remain important considerations. Although potentially severe, these toxicities are generally manageable with early recognition, multidisciplinary care and prompt specialist intervention. As ACT indications expand in Australia, clinician familiarity with indications, mechanisms of action and toxicity profiles is essential to support informed patient discussions, appropriate patient selection, timely referral and prompt toxicity recognition and management. Non‐oncology specialists have an important role in shared care, including patient identification, referral coordination, monitoring for delayed or late toxicities and provision of ongoing survivorship and supportive care. Achieving equitable national access to ACT will require streamlined health technology assessment processes, coordinated reimbursement and delivery funding models and structured referral networks with cross‐institutional collaboration to support the specialised infrastructure required for their delivery.

Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAFV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic BrafV600ECdkn2a−/−Pten−/− melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103+ dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo. While combined BRAF, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma.

Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAFV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic BrafV600ECdkn2a−/−Pten−/− melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103+ dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo. While combined BRAF, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma.

Figure S3 shows that BMP4 does not alter migration or invasion in vitro and that BMP7 can also inhibit metastasis.