Novel treatment and maintenance therapies for multiple myeloma

Multiple myeloma (MM) is a rare cancer of plasma cells, a type of white blood cell in the bone marrow that produces antibodies. Treating MM successfully requires several classes of drugs working together and in many cases a stem cell transplant. In a phase 2 clinical trial conducted by physicians at the University of Chicago Medicine Comprehensive Cancer Center, a four-drug combination (quadruplet) therapy with a novel immunotherapy drug, elotuzumab, added to an existing treatment known as the KRd regimen that consists of carfilzomib, lenalidomide and dexamethasone, was tested.

The results show that more than half (58%) of the patients with newly diagnosed MM had a complete response from the quadruplet therapy, and these findings were published in JAMA Oncology. This is the first time that quadruplet therapy using elotuzumab is being tested in newly diagnosed MM patients. These patients have a 72% probability of being progression-free survival at three years, which is truly among the best results so far, said senior author of the study, Andrzej Jakubowiak, MD, PhD. The promising results of the "quadruplet" therapy suggest that patients might be able to forgo the side effects caused by stem cell transplantation.

Another challenging part of MM treatment is the maintenance therapy usually given to prevent the disease from progression, also called progression-free survival. Jakubowiak's team, in collaboration with colleagues in Poland, has conducted an interim phase 3 ATLAS trial to assess the efficacy and toxicity of triple-drug combination therapy consisting of carfilzomib, lenalidomide and dexamethasone, commonly known as the KRd regimen. The results from this study were recently published in the journal Lancet Oncology, and the interim analysis has indicated an improvement of progression-free survival in comparison with single-agent lenalidomide (53% vs 31%) as a maintenance therapy in newly diagnosed multiple myeloma patients. The efficacy and toxicity results of this study indicate a favorable therapeutic index, making KRd a compelling consideration for post-transplant treatment after autologous stem-cell transplantation, said Jakubowiak, who was the overall principal investigator of the ATLAS study. This study has certain limitations, such as the low number of patients and the interim nature of the published data; however, longer follow-up can confirm the results as well as the treatment outcomes, such as overall tolerability, and survival in high-risk patients.

ORIGINAL ARTICLES

Quadruplet treatment delays the need for stem cell transplantation in newly diagnosed multiple myeloma patients

Study shows promising results for triple-drug therapy for post-transplant management of multiple myeloma

Simultaneous radiation and immunotherapy are beneficial for a subset of lung cancer patients

Recent advances in the development of immune checkpoint blockers have revolutionized the cancer treatment approaches for many cancer conditions, including metastatic non-small cell lung cancer (mNSCLC). Unfortunately, only a fraction of patients have benefited with checkpoint blockers, and a large percent of cancer patients are still in need of better treatment. On the other hand, researchers working with mice had a great success treating cancer with combination treatments of radiation (RT) and immune checkpoint blockade (ICB), which is not the case in humans.

In a recently published Nature Cancer paper, researchers questioned the reason for failure of therapies in human patients. A team led by Sean Pitroda, MD, has conducted a study to identify the biomarker that predicts response to RT and ICB treatment. Authors found that tumors with high aneuploidy scores responded well to the RT and ICB treatment. Aneuploidy is a condition where tumor cells express either missing or extra chromosomes. Interestingly, concurrent treatment (RT given while ICB is on-board) has better outcomes compared to the sequential therapy (RT followed by ICB). The team further tested the utility of aneuploidy as a biomarker in predicting response to the therapy in a larger cohort consisting of 1,660 patients.

The results from this study were published in the journal Nature Genetics and demonstrate the positive association between aneuploidy scores and survival rate after concurrent therapy. Moreover, this is the first time that a method was developed to predict a patient’s response based on a biomarker, which can lead to personalized therapy and the ability to choose the right therapy for the right patient at the right time.

ORIGINAL ARTICLE

Simultaneous radiation and immunotherapy are beneficial for a subset of lung cancer patients

Researchers find new mechanism to turn on cancer-killing T cells

Cancer immunotherapies have emerged as a promising therapeutic option in a wide variety of cancers. Immunotherapies work through the activation of T cells to identify and destroy cancer cells. However, some cancer types or cancer patients are resistant to immunotherapies. The complexity of the immune system and the lack of understanding on how the body mounts an anti-cancer immune response has slowed progress toward making immunotherapies universally efficacious.

Justin Kline, MD, and his team were curious about the role of dendritic cells (the cells that alert the T cells to antigens) in the cancer immune response. The team conducted a study and found that, unlike dendritic cell cross-presentation, in which dendritic cells eat up tumor cells and present antigens to T cells, dendritic cells “dress themselves” with tumor molecules to spur T cells into action. Identifying this pathway might have implications in better designing the next generation of vaccines or which tumor antigens might be best to target. Also, identifying molecular mechanisms behind the cross-dressing and the extent to which cross-dressing can impact dendritic cells’ ability to spur T cells into action have greater practical implications.

ORIGINAL ARTICLE

Researchers find new mechanism to turn on cancer-killing T cells

New I3LUNG project to fund AI tools for improving treatment and outcomes for lung cancer patients

The University of Chicago Medicine has joined the I3LUNG project, a research initiative funded by a five-year, €10M grant from the European Union to develop a decision-making tool for creating individually tailored lung cancer treatment plans. Recently, immunotherapy has been a top choice for treating many cancer conditions; however, less than 30% of patients have a great response to the treatment, thus predicting outcomes to immunotherapy is challenging in the field.

The goal of the 13LUNG project is to utilize artificial intelligence (AI) software and machine learning tools to analyze a wide range of information from clinical data, radiology images and biological characteristics of tumors to predict treatment responses which can help us to better tailor treatments for individual patients, said Marina Garassino, MD, the leader of the University of Chicago Medicine’s arm of the project.

The data will come from 2,000 patients across multiple research centers in the United States, Italy, Germany, Greece, Spain and Israel. At UChicago Medicine, Garassino’s expertise in global lung cancer will be combined with the expertise of Alexander Pearson, MD, PhD, a longtime machine learning scientist and clinician, to leverage the emerging methods and try to build an algorithm and train the AI to find a signature that will predict the effectiveness of immunotherapy for any given patient. Ultimately, the hope is that the tools developed by the I3LUNG project can be applied to not only non-small cell lung cancer treatments, but other types of cancers and treatments.

ORIGINAL ARTICLE

New I3LUNG project to fund AI tools for improving treatment and outcomes for lung cancer patients

“Bridge therapy” may benefit some children with high-risk neuroblastoma

Neuroblastoma is a childhood cancer of immature nerve cells that mainly affects infants and young children. Treatment for these children often includes chemotherapy, surgery, radiation therapy, stem cell transplant, retinoid therapy and immunotherapy. Despite remission after the initial induction therapy (various chemotherapy drugs plus surgery) followed by consolidation therapy (high dose of chemotherapy plus stem cell transplants), approximately half of the high-risk children experience recurrence or relapse. In these cases, a bridge therapy which includes a combination of immunotherapy drugs with other therapies could offer some benefit. Ami V. Desai, MD, MSCE, and her colleagues have examined the benefits of bridge therapy strategy in 201 neuroblastoma patients. They found that patients who received bridge therapy prior to consolidation therapy with stable tumors after induction therapy had significantly improved event-free survival compared to the patients who went directly to consolidation therapy. The findings from this study suggest that bridge therapy prior to consolidation therapy benefits high-risk neuroblastoma patients who do not experience a favorable outcome following standard induction therapy.

ORIGINAL ARTICLE

“Bridge therapy” may benefit some children with high-risk neuroblastoma

Increased mitochondria and lipid turnover reduces risk for liver cancer

Hepatocellular carcinoma, the most common form of liver cancer, is known to be caused by alcohol consumption and hepatitis C viral infection. Apart from these known risk factors, nonalcoholic fatty liver disease has emerged as a major contributing factor causing hepatocellular carcinoma in Western societies. The mechanisms underlying obesity-induced liver cancer are not well understood.

A new study published in the journal Science Advances by University of Chicago researchers demonstrated that deletion of a particular protein called BNIP3 in mice caused lipid accumulation and development of fatty liver and, ultimately, liver cancer. Normally, BNIP3 levels were significantly increased in the liver in response to fasting in mice, protecting liver from fat accumulation. However, we don’t know the underlying mechanisms of how BNIP3 is regulating the lipid levels in liver, said Kay Macleod, PhD, senior author of the paper.

In the fatty liver condition, excess lipid accumulates in the liver cells, causing cell death, which further leads to generation of new liver cells. If this process continues in an uncontrolled way, that may result in hepatocellular carcinoma. For growing or multiplying cells, it requires a lot more membrane consisting of phospholipids. BNIP3 will limit the number of phospholipids in the cell, thereby limiting the lipids required for new cell generation.

The study from Macleod’s team suggests BNIP3 is critical in both preventing initiation of tumors and also limiting progression of tumors that are already formed by preventing them growing faster or becoming more aggressive. Much attention has been paid to tumor metabolism, especially to amino acids and glucose metabolism; however, understanding how lipid metabolism is deregulated in cancers is also important to successfully treat non-alcoholic fatty liver induced liver cancers.

ORIGINAL ARTICLE

Increased mitochondria and lipid turnover reduces risk for liver cancer