Treatment duration with immune-based therapies in Cancer: an enigma

Abstract Unlike chemotherapy treatments that target the tumor itself (rather nonspecifically), immune-based therapies attempt to harness the power of an individual patient’s immune system to combat cancer. Similar to chemotherapeutic agents, the dosage and Administration section of labeling for all five currently approved PD-1/PD-L1 inhibitors (immunotherapy) recommends duration of treatment until disease progression or unacceptable toxicity. Overactivation or constitutive activation of the immune system with immune based therapies can lead to T-cell exhaustion and activation induced cell death (AICD) in T- and B-cells. Examples of immune exhaustion and T-cell depletion is noted in preclinical and clinical studies. Overactivation or constitutive activation leading to Immune exhaustion is a real phenomenon and of profound concern as immune cells are the true arsenal for control of the tumor growth. Designing trials rigorously to address the optimum treatment duration with immune based therapies is critical. By addressing this concern now, not only we may improve patient outcomes, but also gather a deeper understanding of the role and mechanisms of the immune system in the control of tumor growth. Chemotherapy and immune-based therapies provide antitumor effects through completely different mechanisms. Chemotherapeutic agents are cytotoxic in that they directly inhibit basic cellular mechanisms, killing both malignant and nonmalignant cells (hopefully with a preference for malignant cells), while immune based therapies wake-up the host immune system to recognize malignant cells and eliminate them. While there is a burgeoning excitement surrounding development of immune based therapies for the treatment of cancer, the optimal duration for these therapies need to be explored with equal fervor. Dosing for chemotherapy has been determined over years through large-scale prospective randomized trials to pinpoint the dose which maximizes therapeutic effect while minimizing side effects. Also, due to the mechanism of chemotherapeutic action, the duration of treatment with these agents is generally until disease progression or patient intolerance. However, experience with immune based therapies is limited, with current dosing and duration guidelines based primarily on initial trials required for approval of the agents. Since immune based therapies work by activating the body’s own immune system, there is concern that overactivation or constitutive activation of the immune system may lead to immune exhaustion and depletion of effector T-cells thereby causing decreased anti-tumor effects and possible allowing for tumor progression. Similar to chemotherapeutic agents, the Dosage and Administration section of labeling for all five currently approved PD-1/PD-L1 inhibitors recommends duration of treatment until disease progression or unacceptable toxicity. However, since immune based therapies work with a completely different mechanism compared to chemotherapy, using the same therapy duration may not be the optimal approach. In exploring treatment duration with immune based therapies, we need to answer the following: (1) does indefinite treatment with immune based therapies exhaust the immune system counteracting its own mechanism of action leading to tumor progression and (2) how can clinical trials be designed to identify the optimal duration of immune-based therapy that prevents immune cell exhaustion but supports anti-tumor immunity

Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM

Chronic lymphocytic leukemia (CLL) is an incurable disease derived from the monoclonal expansion of CD5(+) B lymphocytes. High expression levels of ZAP-70 or CD38 and deletions of 17p13 (TP53) and 11q22-q23 (ATM) are associated with poorer overall survival and shorter time to disease progression. DNA damage and p53 play a pivotal role in apoptosis induction in response to conventional chemotherapy, because deletions of ATM or p53 identify CLL patients with resistance to treatment. Forodesine is a transition-state inhibitor of the purine nucleoside phosphorylase with antileukemic activity. We show that forodesine is highly cytotoxic as single agent or in combination with bendamustine and rituximab in primary leukemic cells from CLL patients regardless of CD38/ZAP-70 expression and p53 or ATM deletion. Forodesine activates the mitochondrial apoptotic pathway by decreasing the levels of antiapoptotic MCL-1 protein and induction of proapoptotic BIM protein. Forodesine induces transcriptional up-regulation of p73, a p53-related protein able to overcome the resistance to apoptosis of CLL cells lacking functional p53. Remarkably, no differences in these apoptotic markers were observed based on p53 or ATM status. In conclusion, forodesine induces apoptosis of CLL cells bypassing the DNA-damage/ATM/p53 pathway and might represent a novel chemotherapeutic approach that deserves clinical investigation

A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)

The discovery of purine nucleoside phosphorylase (PNP) deficiency and T lymphocytopenia suggested that inhibition of this enzyme could serve as a therapeutic target. Inhibitors of PNP failed until structure-based synthesis of immucillin-H (BCX-1777, forodesine), a transition-state analog of PNP. The picomolar potency for PNP, T cell-selective cytotoxicity, and animal studies provided the rationale for use of forodesine in T-cell malignancies. Five patients were treated with an intravenous infusion of forodesine (40 mg/m2) on day 1; treatment continued on day 2; forodesine was administered every 12 hours for an additional 8 doses. Plasma and cellular pharmacokinetics and pharmaco-dynamics were investigated. Median peak level of forodesine (5.4 μM) was achieved at the end of infusion. This level was sufficient to increase plasma 2′-deoxyguanosine (dGuo) concentrations in all patients. Intracellular deoxyguanosine triphosphate (dGTP) increased by 2- to 40-fold in 4 of 5 patients (8 of 9 courses) and correlated with antileukemia activity in 4 patients. However, objective responses were not observed. This was the first clinical study in humans to demonstrate the plasma pharmacokinetics and the pharmacodynamic effectiveness of the PNP inhibitor, forodesine; however, regrowth of leukemia cells in the blood and marrow after course 1 suggested that a different therapeutic schedule should be considered for future studies

In vitro efficacy of forodesine and nelarabine (ara-G) in pediatric leukemia

Forodesine and nelarabine (the pro-drug of ara-G) are 2 nucleoside analogues with promising anti-leukemic activity. To better understand which pediatric patients might benefit from forodesine or nelarabine (ara-G) therapy, we investigated the in vitro sensitivity to these drugs in 96 diagnostic pediatric leukemia patient samples and the mRNA expression levels of different enzymes involved in nucleoside metabolism. Forodesine and ara-G cytotoxicities were higher in T-cell acute lymphoblastic leukemia (T-ALL) samples than in B-cell precursor (BCP)-ALL and acute myeloid leukemia (AML) samples. Resistance to forodesine did not preclude ara-G sensitivity and vice versa, indicating that both drugs rely on different resistance mechanisms. Differences in sensitivity could be partly explained by significantly higher accumulation of intra-cellular dGTP in forodesine-sensitive samples compared with resistant samples, and higher mRNA levels of dGK but not dCK. The mRNA levels of the transporters ENT1 and ENT2 were higher in ara-G-sensitive than -resistant samples. We conclude that especially T-ALL, but also BCP-ALL, pediatric patients may benefit from forodesine or nelarabine (ara-G) treatment