Hypomethylating Agent-Based Combination Therapies to Treat Post-Hematopoietic Stem Cell Transplant Relapse of Acute Myeloid Leukemia

Allogeneic stem cell transplantation still represents the best curative option for most patients with acute myeloid leukemia, but relapse is still dramatically high. Due to their immunologic activity and safety profile, hypomethylating agents (HMAs) represent an interesting backbone for combination therapies. This review reports mechanism of action, safety, and efficacy data on combination strategies based on HMAs in the setting of post-allogeneic stem cell transplant relapse. Several studies highlighted how HMAs and donor lymphocyte infusion (DLI) combination may be advantageous. The combination strategy of HMA with venetoclax, possibly in association with DLI, is showing excellent results in terms of response rate, including molecular responses. Lenalidomide, despite its well-known high rates of severe graft-versus-host disease in post-transplant settings, is showing an acceptable safety profile in association with HMAs with a competitive response rate. Regarding FLT3 internal tandem duplication (ITD) mutant AML, tyrosine kinase inhibitors and particularly sorafenib have promising results as monotherapy and in combination with HMAs. Conversely, combination strategies with gemtuzumab ozogamicin or immune checkpoint inhibitors did not show competitive response rates and seem to be currently less attractive strategies. Associations with histone deacetylase inhibitors and isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors represent new possible strategies that need to be better investigated.

Combinatorial Therapeutic Approaches with Nanomaterial-Based Photodynamic Cancer Therapy

Photodynamic therapy (PDT), in which a light source is used in combination with a photosensitizer to induce local cell death, has shown great promise in therapeutically targeting primary tumors with negligible toxicity and minimal invasiveness. However, numerous studies have shown that noninvasive PDT alone is not sufficient to completely ablate tumors in deep tissues, due to its inherent shortcomings. Therefore, depending on the characteristics and type of tumor, PDT can be combined with surgery, radiotherapy, immunomodulators, chemotherapy, and/or targeted therapy, preferably in a patient-tailored manner. Nanoparticles are attractive delivery vehicles that can overcome the shortcomings of traditional photosensitizers, as well as enable the codelivery of multiple therapeutic drugs in a spatiotemporally controlled manner. Nanotechnology-based combination strategies have provided inspiration to improve the anticancer effects of PDT. Here, we briefly introduce the mechanism of PDT and summarize the photosensitizers that have been tested preclinically for various cancer types and clinically approved for cancer treatment. Moreover, we discuss the current challenges facing the combination of PDT and multiple cancer treatment options, and we highlight the opportunities of nanoparticle-based PDT in cancer therapies.

A Promising Treatment Strategy for Lung Cancer: A Combination of Radiotherapy and Immunotherapy

Lung cancer is a leading cause of cancer-related deaths worldwide despite advances in treatment. In the past few decades, radiotherapy has achieved outstanding technical advances and is being widely used as a definitive, prophylactic, or palliative treatment of patients with lung cancer. The anti-tumor effects of radiotherapy are considered to result in DNA damage in cancer cells. Moreover, recent evidence has demonstrated another advantage of radiotherapy: the induction of anti-tumor immune responses, which play an essential role in cancer control. In contrast, radiotherapy induces an immunosuppressive response. These conflicting reactions after radiotherapy suggest that maximizing immune response to radiotherapy by combining immunotherapy has potential to achieve more effective anti-tumor response than using each alone. Immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1/programmed death-ligand 1, and their inhibitors, have attracted significant attention for overcoming the immunosuppressive conditions in patients with cancer. Therefore, the combination of immune checkpoint inhibitors and radiotherapy is promising. Emerging preclinical and clinical studies have demonstrated the rationale for these combination strategies. In this review, we outlined evidence suggesting that combination of radiotherapy, including particle therapy using protons and carbon ions, with immunotherapy in lung cancer treatment could be a promising treatment strategy.

Watt-Level Ka-Band Integrated Doherty Power Amplifiers: Technologies and Power Combination Strategies Invited Paper

This paper discusses some of the design choices underlying the development of watt-level integrated Doherty power amplifiers in the K and Ka band, focusing on compound semiconductor technologies. The key aspect of on-chip power combination is discussed, presenting and comparing some of the possible alternatives. Then, the impact on the achievable bandwidth and performance of different parameters is quantified, adopting an approximate analysis, which focuses on the Doherty output combiner and allows estimating the non-linear performance of the amplifier thanks to some simplifying assumptions, without requiring a full, non-linear model of the active devices. Two sample GaAs and GaN technologies are compared first, considering parameters that are representative of the currently available commercial processes, and then several power combination strategies are analyzed, adopting the GaN technology, which is currently the only one that allows achieving the power levels required by the applications directly on chip. Finally, some hints as to the impact of the output parasitic effects of the transistors on the presented analysis are given.

HDAC Inhibition to Prime Immune Checkpoint Inhibitors

Immunotherapy has made a breakthrough in medical oncology with the approval of several immune checkpoint inhibitors in clinical routine, improving overall survival of advanced cancer patients with refractory disease. However only a minority of patients experience a durable response with these agents, which has led to the development of combination strategies and novel immunotherapy drugs to further counteract tumor immune escape. Epigenetic regulations can be altered in oncogenesis, favoring tumor progression. The development of epidrugs has allowed targeting successfully these altered epigenetic patterns in lymphoma and leukemia patients. It has been recently shown that epigenetic alterations can also play a key role in tumor immune escape. Epidrugs, like HDAC inhibitors, can prime the anti-tumor immune response, therefore constituting interesting partners to develop combination strategies with immunotherapy agents. In this review, we will discuss epigenetic regulations involved in oncogenesis and immune escape and describe the clinical development of combining HDAC inhibitors with immunotherapies.

Bcl2 inhibitor venetoclax +/− Anti-CD20: what do deep remissions mean?

SummaryIn recent years, treatment of patients exhibiting chronic lymphocytic leukemia has changed extensively due to advances in the development of targeted therapies. The Bcl‑2 inhibitor venetoclax demonstrated outstanding results when used in mono- as well as combination therapy. Minimal residual disease (MRD) measurement has become an important endpoint in most studies and shows high prognostic potential. With upcoming combination strategies, the role of MRD measurement has also increased and is likely to become a routine marker in future clinical practice.

Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer

In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC.

Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Combinations of inhibitors of Ataxia Telangiectasia- and Rad3-related kinase (ATRi) and poly(ADP-ribose) polymerases (PARPi) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this we performed a genome-wide CRISPR/Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations or the Alternative Lengthening of Telomeres telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. Altogether, we present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.