A roadmap for effective treatment of COVID-19

Study outlines key immunological factors underlying COVID-19 disease progression and proposes a range of drugs that may be repurposed to treat the disease

Due to the devastating worldwide impact of COVID-19, the illness caused by the SARS-CoV-2 virus, there has been unprecedented efforts by clinicians and researchers from around the world to quickly develop safe and effective treatments and vaccines. Given that COVID-19 is a complex new disease with no existing vaccine or specific treatment, much effort is being made to investigate the repurposing of approved and available drugs, as well as those under development.

In Frontiers in Immunology, a team of researchers from the U.S. Food and Drug Administration review all of the COVID-19 clinical and research findings to date. They provide a breakdown of key immunological factors underlying the clinical stages of COVID-19 illness that could potentially be targeted by existing therapeutic drugs.

Dr. Montserrat Puig of the U.S. Food and Drug Administration, senior author of the review, stated that “there are multiple factors involved in determining if the patient’s immune response will be insufficient or successful in combating the infection. Our review is an overview of these factors and how they can be considered to define the context in which medications currently used for other diseases, or development of novel agents, can be utilized to prevent, ameliorate or cure COVID-19.”

We know that during the early stage of COVID-19 people can show no symptoms or mild symptoms, and for many the disease resolves.

For others it can be catastrophic. The illness can progress to a severe stage with manifestations including Acute Respiratory Distress Syndrome, accompanied by severe lung inflammation and damage. Patients with severe COVID-19 are often admitted to intensive care units and require life support with medical ventilation.

This review compiles and summarizes published up-to-date studies unraveling the factors leading to the cytokine storm and its consequences observed in COVID-19, including the immunological events underlying the severe manifestation of the disease.

The analysis is further supplemented with knowledge previously acquired from other coronaviruses including SARS-CoV and MERS-CoV.

The authors underscore key immunological events that might tip the balance from a protective to a hyperinflammatory response leading to life-threatening conditions. They outline a promising list of currently available drugs that are either under study or under consideration for use in COVID-19 based on their potential to influence these key immunological events.

These drugs include those that could inhibit SARS-CoV-2 entry into host cells, antivirals with the potential to block SARS-CoV-2 replication or factors that could boost the antiviral response, monoclonal antibodies targeting pro-inflammatory cytokines that drive the hyperinflammatory response and therapeutics that could improve the function of the lungs.

Puig states that “approaches to therapy in the early stage of the disease will differ from those in its severe late stage.” Adding that “as the results of clinical trials become available, it may become increasingly clear that there is likely no single magic bullet to resolve the disease but a combination of several interventions that target different key factors of COVID-19 may well be required.”

Puig cautions that “the research and data obtained from COVID-19 studies are rapidly evolving and continuously updated. Thus, as clearly stated in our review, the information provided is a ‘lessons learned’ to date and describes the knowledge available at the time of the publication of the review.”

The description of the immunological profile of the clinical stages of COVID-19 provided in this review will enable more informed decisions about the type and timing of treatments to be evaluated in clinical trials.

Puig explains that “our hope is that the information contained in our review will help professionals in COVID-19 research develop new tools and agents to better treat those at high risk of severe COVID-19.”

Press release on the roadmap for the COVID-19 treatment from Frontiers

Study shows immunotherapy prior to surgery may help destroy high-risk breast cancer

New Haven, Conn. — A new study led by Yale Cancer Center (YCC) researchers shows women with high-risk HER2-negative breast cancer treated before surgery with immunotherapy, plus a PARP inhibitor with chemotherapy, have a higher rate of complete eradication of cancer from the breast and lymph nodes compared to chemotherapy alone. The findings, part of the I-SPY clinical trial, were presented today at the American Association for Cancer Research (AACR) virtual annual meeting.

immunotherapy breast cancer — A new study led by Dr. Lajos Pusztai of Yale Cancer Center shows immunotherapy prior to surgery may help destroy high-risk breast cancer. Credit: Yale Cancer Center

“The results provide further evidence for the clinical value of immunotherapy in early stage breast cancer and suggest new avenues to use these drugs, particularly in estrogen receptor (ER)-positive/HER2-negative breast cancers,” said Lajos Pusztai, M.D., Professor of Medicine (Medical Oncology) and Director of Breast Cancer Translational Research at YCC. Pusztai presented the results of the study today during a plenary session at the AACR meeting.

Physicians treat some women with HER-2 negative breast cancer with chemotherapy before surgery, hoping to shrink the tumor and to guide treatment after the operation. In a subgroup of women, this pre-surgical treatment destroys any evidence of the tumor, achieving what is called “pathologic complete response” (pCR), a condition that typically heralds increased overall survival.

Investigators in the I-SPY 2 clinical trial now report that for women with HER2-negative breast cancer who are treated before surgery, an average pCR rate rises from 22% among those given standard-of-care chemotherapy to 37% in those who received the immunotherapy drug durvalumab, plus the PARP inhibitor drug olaparib, in addition to chemotherapy.

Durvalumab is a checkpoint inhibitor immunotherapy, engineered to unleash immune system T cells against tumors by inhibiting a protein on the surface of T cells called PD-1. PARP inhibitor drugs such as olaparib aim to the ability of impair cancer cells to repair DNA damage caused by chemotherapy.

Overall, 73 patients in the experimental arm were given durvalumab, olaparib, and paclitaxel chemotherapy followed by doxorubicin/cyclophosphamide chemotherapy, while 229 patients in the control arm received the standard treatment of paclitaxel plus doxorubicin/ cyclophosphamide. Researchers analyzed results for all HER2-negative patients, as well as for triple-negative (TNBC) and ER positive subsets. Women with triple negative cancer who received the combination treatment saw a pCR rate of 47%, compared to those given the standard chemotherapy with a pCR rate of 27%. Patients with estrogen-positive/HER2-negative cancer in the experimental arm experienced a pCR rate of 28%, versus 14% for those in the control arm. Patients in the experimental arm, however, were also more likely to experience grade 3 serious adverse events–58% in the experimental arm compared to 41% in the control arm.

Immune-rich cancers showed higher pCR rates in all subtypes and in both treatment arms, but the investigators discovered biomarkers that potentially could identify patients who are most likely to benefit from treatment with durvalumab and olaparib. Among estrogen-positive/HER2-negative cancers, the MammaPrint ultra-high subset benefited the most from the combination, their pCR rate reached 64%. In TNBC, tumors with low CD3/CD8 ratio, high Macrophage/Tcell-MHC class II ratio, and high proliferation appear to have benefited preferentially from adding durvalumab and olaparib to paclitaxel.

I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) 2 is a multicenter phase 2 trial to evaluate novel agents as pre-surgical therapy for breast cancer. The study is a collaboration among 20 U.S. cancer research centers, the U.S. Food and Drug Administration and the Foundation for the National Institutes of Health Cancer Biomarkers Consortium. Lead support for I-SPY 2 came from the Quantum Leap Healthcare Collaborative.

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About Yale Cancer Center and Smilow Cancer Hospital

Yale Cancer Center (YCC) is one of only 51 National Cancer Institute (NCI-designated comprehensive cancer) centers in the nation and the only such center in Connecticut. Cancer treatment for patients is available at Smilow Cancer Hospital through 13 multidisciplinary teams and at 15 Smilow Cancer Hospital Care Centers in Connecticut and Rhode Island. Smilow Cancer Hospital is accredited by the Commission on Cancer, a Quality program of the American College of Surgeons. Comprehensive cancer centers play a vital role in the advancement of the NCI’s goal of reducing morbidity and mortality from cancer through scientific research, cancer prevention, and innovative cancer treatment.

Press release from the Yale Cancer Center, Yale University

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