Mechanistic and pharmacologic insights on immune checkpoint inhibitors

Abstract

The concept of augmenting the immune system to eradicate cancer dates back at least a century. A major resurgence in cancer immunotherapy has occurred over the past decade since the identification and targeting of negative regulators with antibody therapies to augment the anti-tumor immune response. Unprecedented responses across a broad array of cancer types elevated this class of therapies to the forefront of cancer treatment. The most successful drugs to date target the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) pathways. The immune biology of these pathways was illuminated through thoughtful pre-clinical experiments over the past 20 years. The characterization of these negative immune regulators, also known as immune checkpoints, subsequently led to the successful clinical development four drugs in six different cancer types to date, and progress continues. Despite these successes, significant challenges remain including the development of predictive biomarkers, recognition and management of immune related toxicities, and elucidating and reversing mechanisms of primary and secondary resistance. Ongoing work is expected to build upon recent accomplishments and allow more patients to benefit from this class of therapies.

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

“…33 Duokines are not restricted to cancer therapy but might also be beneficially applied in other indications, such as viral infections, especially those being latent or chronic in nature. 34,35 Because of their modular structure, the duokine strategy described here allows combining different members of the co-stimulatory TNFSF family and thus, enables to specifically tailor the immunological responses to the therapeutic requirements.…”

Fibrotic lung toxicity induced by cytotoxic drugs, radiation and immunotherapy in patients treated for lung cancer

“…In the last few years some studies have reported the utility of KL 6 for the evaluation of DILD. KL 6 is typically elevated in patients with idiopathic interstitial pneumonia and in certain cases of cancer, and may therefore be useful for evaluating disease activity and clinical outcome in patients with ILD-IPF: it could predict the likelihood of radiation pneumonitis or lung toxicity induced by chemotherapy [15][16][17][18][19][20]. Recently, a similar predictive role of Surfactant Protein D (SP-D) for onset of ILD induced by anticancer agents was compared with KL 6 in an interesting case control study [18].…”

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“…Programmed death-ligand 1 (PD-L1) is a transmembrane protein that binds to the programmed death-1 receptor (PD-1) during immune system modulation. The PD-1 receptor is typically expressed on cytotoxic T-cells and other immune cells while PD-L1 ligand is typically expressed on normal cells [31]. Under normal conditions, cells use the PD-1/PD-L1 interaction as a mechanism of protection against immune recognition via inhibiting the action of T-cells thus downregulating the immune response such that inactive T-cells are exhausted, cease to divide and eventually die by programmed cell death or apoptosis [30].…”

“…Under normal conditions, cells use the PD-1/PD-L1 interaction as a mechanism of protection against immune recognition via inhibiting the action of T-cells thus downregulating the immune response such that inactive T-cells are exhausted, cease to divide and eventually die by programmed cell death or apoptosis [30]. Studies have shown that numerous types of tumor cells upregulate the expression of PD-L1 as a mechanism to evade the immune response [31]. Activated T-cells recognize the PD-L1 marker on the tumor cell (similar to that of a normal cell) and render the cytotoxic T-cell inactive and thus the tumor cell escapes the immune cycle for elimination and is able to proliferate [31].…”

“…Studies have shown that numerous types of tumor cells upregulate the expression of PD-L1 as a mechanism to evade the immune response [31]. Activated T-cells recognize the PD-L1 marker on the tumor cell (similar to that of a normal cell) and render the cytotoxic T-cell inactive and thus the tumor cell escapes the immune cycle for elimination and is able to proliferate [31]. Despite a tremendous thrust of anti PD-1 and PDL-1 agents, the realm of neuroendocrine tumors (NETs) seems to be relatively untouched.…”