Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

T-cell programming in pancreatic adenocarcinoma: a review.

Despite recent advancements in multimodal therapy, pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. In the era of burgeoning immune therapies against previously difficult-to-treat malignancies, there has been growing interest in activating the immune system against PDA; however, unlike in other cancers such as melanoma and lymphoma, immunotherapy has not yielded many clinically significant results. To harness these mechanisms for therapeutic use, an in-depth understanding of T-cell programming in the immune microenvironment of PDA must be achieved. The outcome of T-cell programming against pathogens or cancer depends on the uptake and presentation of foreign antigens by dendritic cells and macrophages to T cells, and the expression of various co-stimulatory molecules and cytokines. Subsequent immune responses are kept in check via regulatory mechanisms such as immune checkpoints (for example, programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4)), as well as other immunosuppressive cell types such as regulatory T cells (Treg) and M2 macrophages. PDA presents a challenge from the perspective of immune therapy because of many immunosuppressive mechanisms at play in its microenvironment. The tumor itself produces IL-10 and transforming growth factor beta (TGF-ß) that downregulate T-cell activation as well as the activity of antigen-presenting cells. At the same time, PDA also appears to recruit more regulatory elements into its milieu; higher infiltration of Treg, for instance, has been associated with poorer prognosis in PDA patients. M2 macrophages and myeloid-derived suppressive cells are also highly prevalent in the tumor microenvironment. T cells in PDA have high expression of PD-1, whereas the tumor has high expression of PD-L1, which likely inhibits activation of tumor antigen-specific T cells. Many of these immunosuppressive mechanisms have been targeted as potential immune therapies of PDA. Immune checkpoint inhibitors, which target PD-1 and CTLA-4, have been shown to be effective in other cancers such as melanoma; however, they have not demonstrated outcome benefits in PDA so far. Other novel investigational approaches under study currently include inhibiting the homing of immunosuppressive cell types to the tumor milieu, as well as vaccines designed to boost the adaptive response to PDA antigens. As our understanding of the nuanced and complex interactions of the immune microenvironment expands, more targeted approaches can be taken toward achieving therapeutic success in immune therapy against PDA.