Starting the second day of the 2020 Annual Meeting of the American Association for Cancer Research (AACR 2020), a record-breaking 61,000 registrants heard from experts at major cancer centers in COVID-19 hotspots around the world regarding what they’ve learned so far about the novel coronavirus (SARS-CoV-2) and its impact on cancer patients.
COVID-19 and Cancer
While some consistent patterns are becoming evident, experts stressed that much of the early data we have are still preliminary and incomplete, and that this is a situation that will continue to evolve as we learn more about this virus and the factors that cause severe disease in certain patients.
Speaking from Wuhan, China, which saw the first reported cases of severe COVID-19, Li Zhang, M.D., of Tongji Medical College, dissected data from 1,276 cancer patients who had been infected with the novel coronavirus and showed that, compared to patients with other types of cancer, lung cancer patients had a 27.3 percent increased risk of severe illness.
Additionally, in a smaller retrospective analysis of 28 cancer patients with severe COVID-19 demonstrated that people with any type of stage 4 cancer had a 49.1 percent greater risk than those with stage 3 or lower. Other factors associated with increased risk of severe events included being older than 65 years, genetically male, and having had received an anti-tumor therapy within two weeks before being diagnosed with COVID-19. While the data still preliminary, there is no indication that having been treated with checkpoint immunotherapy for cancer posed an increased risk of infection or severe disease.
Hongbing Cai, M.D., of the Zhongnan Hospital of Wuhan University, showed that another analysis found that COVID-19-infected cancer patients were at greater risk of severe illness. Like Zhang, Cai demonstrated a link to metastatic disease and lung cancer. In addition, she pointed to worse outcomes in patients with blood cancer, a trend also noted by Fabrice Barlesi, M.D., Ph.D., of Gustave Roussy Cancer Campus in Paris, another city that has also been significantly impacted by the current crisis.
Joining from Italy, Marina Chiara Garassino, M.D., of the Istituto Nazionale dei Tumori in Milan discussed a collaborative global registry of lung cancer patients with COVID-19 called TERAVOLT, which found an unexpectedly high 34.6 percent rate of death among cancer patients that was largely attributed to coronavirus infection, rather than cancer.
Garassino and others, including Paolo A. Ascierto, M.D., of the Istituto Nazionale dei Tumori in Naples, Italy, discussed how hospitals’ efforts to discourage all but the most critically ill patients from seeking medical treatment is having an impact on regular inpatient services for cancer patients who may need it most. Cancer patients at less critical stages of disease, however, may be able to postpone in-patient treatment or, whenever possible, receive oral medicines instead of intravenous drugs.
Garassino also acknowledged that the longer the pandemic persists without an effective treatment or preventive measure such as a vaccine, the greater the risks cancer patients face by delaying treatment. The equation will change, she said, and already has for some, but only time will tell when every cancer patient can resume normal course of care.
Speaking from Madrid, Spain, Carlos Gomez-Martin, M.D., Ph.D., of Octubre University Hospital, discussed the potential role of cytokine release syndrome (CRS), a severe immune inflammation that can attack organs including the lungs, in some deaths due to COVID-19. Several clinical trials are investigating drugs that block the IL-6 pathway involved in inflammation, but it is too early still to draw conclusions. In addition to closely monitoring inflammatory parameters to track CRS, Gomez-Martin also stressed that treating COVID-19 patients with drugs to reduce the risk of blood clots should be appropriately considered by physicians given that these patients are at higher risk for potentially harmful blood coagulation.
From New York City, the city hardest-hit by the COVID-19 pandemic, Louis P. Voigt, M.D., of Memorial Sloan Kettering Cancer Center drew attention to the racial and ethnic disparities in treatment outcomes for COVID-19 patients. According to Voigt, throughout NYC and New York State, disproportionately more African Amercans (and to a lesser extent, Latin Americans) diagnosed with COVID-19 had more severe illness and worse clinical outcomes than patients of other races or ethnicities. This inequality in treatment outcomes may be linked to previously described disparities in access to quality health care, prompting Voigt to suggest that systemic reforms will be necessary to address this issue.
Cellular Immunotherapies Against Cancer
Following this update on global efforts against COVID-19 was a session featuring several promising cellular immunotherapies against cancer.
Haneen Shalabi, D.O., of the National Cancer Institute, presented results from a trial in which a dual CD19/CD22-targeting CAR T cell therapy was used to treat patients with B cell cancers—specifically children and adults with relapsed or refractory acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). Twelve of eight patients responded, including five complete responses with no signs of residual disease in the bone marrow (MRD-negative). While CAR T cell expansion was seen in all responders, relapse occurred in patients without the loss of the CD19 and CD22 antigens, suggesting these living drugs weren’t able to maintain their functionality long-term.
A small study testing a “universal” CAR T cell product that is made from donor cells and targets the CD7 receptor was discussed by Xinxin Wang, Ph.D., of Gracell Biotechnologies. Five patients with relapsed or refractory T cell leukemia had complete responses (although one eventually relapsed). Four patients experienced cytokine release syndrome (CRS), but doctors were able to bring it under control. Evidence suggests that durability of clinical benefit, however, may be an issue here, too.
In discussing these CAR T cell strategies, CRI Lloyd J. Old STAR Yvonne Chen, Ph.D., of the University of California, Los Angeles, went over how we might use genomic engineering tools to improve the persistence of CAR T cells, such as by programming them to be able to better withstand the immunosuppression found within tumor environments. (For a more detailed look at these factors and how she’s addressing them, check out Dr. Chen’s recent interview with CRI.)
Other presenters discussed tumor-infiltrating lymphocyte, or TIL, therapies that target markers known as neoantigens that are unique to an individual patient’s tumors. Ben Creelan, M.D., of the H. Lee Moffitt Cancer Center, spoke about one TIL therapy trial being led by former CRI Clinical Team Leader Scott J. Antonia, M.D., Ph.D., also at Moffitt. Antonia and his team were able to successfully expand cancer-specific T cells—both CD4-positive and CD8-positive—from the tumors of nineteen of twenty patients with metastatic non-small cell lung cancer (NSCLC), the most common form of lung cancer.
Sixteen patients eventually received the TIL therapy after not responding to nivolumab (Opdivo®), a PD-1 checkpoint immunotherapy, and two had complete responses that remain ongoing. An additional two, possibly three, patients have had partial responses, although it remains too early to determine whether this treatment increases overall survival. Another TIL-based cell therapy that relies on a sophisticated target prediction and cell manufacturing platform—known as VELOSTM—was discussed by Edward Samuel, Ph.D., of Achilles Therapeutics.
The potential of these cutting-edge, personalized cell therapies for patients was put into perspective by Theodore Roth, Ph.D., who works in the lab of CRI Lloyd J. Old STAR Alexander Marson, M.D., Ph.D., at the University of California, San Francisco. The combination of novel genome engineering tools like CRISPR—which Marson’s lab specializes in—combined with improved analytical and manufacturing systems, has brought us to an exciting point.
Now, according to Roth, we can switch the traditional cell therapy discovery pipeline, which normally begins with manipulating genes and then seeing how these genetic changes influence the behavior of cells. Now, he said, we can start with how we want T cells to look and behave, and then work backwards to determine the genetic programs needed to elicit this desired activity. By doing so, we might soon be able to significantly accelerate the process of discovery and decrease time needed to develop next generation cell therapies. (For more on the future of cell therapy and how he’s helping to bring it about, read Dr. Marson’s recent interview with CRI.)
In preclinical work, Davide Bernareggi, Ph.D., of the University of California, San Diego, explored a pathway that might provide a way to improve the effectiveness of natural killer (NK) cell-based immunotherapies. In mice, knocking out the CHMP2A gene in cancer cells increased killing of NK cell-mediated tumor elimination. These CHMP2A-deficient cancer cells were also shown to secrete higher levels of molecules that attract and activate NK cells, suggesting it might be a beneficial target for enhancing the anti-cancer activity of NK cells.
Checkpoint Immunotherapy Insights
Unsurprisingly, checkpoint inhibitor immunotherapies, both alone and in combination, came up again on day two of AACR20.
But one thing that was surprising was when the data shown in one presentation—by Merck’s Mallika Lala, Ph.D.—coincided with an FDA approval announcement the very same day. Pembrolizumab (Keytruda®) is already approved in metastatic melanoma. But now, instead of treating patients every three weeks, they can receive double the dose every six weeks. Forty-four patients were treated with this new regimen, which appeared equally effective and was associated with a similar side effect profile.
Andrew X. Zhu, M.D., Ph.D., of Massachusetts General Hospital and Jiahui International Cancer Center, identified biomarkers associated with clinical benefit in liver cancer patients treated with the combination of the anti-PD-L1 atezolizumab (Tecentriq®) plus bevacizumab (Avastin®), a targeted antibody that blocks tumor blood vessel growth and may help overcome immunosuppression in the tumor microenvironment.
Compared to the standard-of-care chemotherapy sorafenib (Nexavar®), this combination has been shown to improve overall survival and reduce risk of death by 42 percent in patients with unresectable and previously untreated liver cancer. In particular, people with high levels of PD-L1 and activated T cells were more likely to respond and had longer progression-free survival. Compared to atezolizumab alone, responses to the combination appeared to be linked with inflamed myeloid immune cells as well as regulatory T cells, which can also suppress cancer-killing T cells.
Stephen Mok, Ph.D., a CRI postdoctoral fellow in the lab of CRI Scientific Advisory Council Director and Nobel Laureate James P. Allison, Ph.D., at the University of Texas MD Anderson Cancer Center, unveiled insights into the combination of anti-PD-1 and anti-CTLA-4 checkpoint immunotherapy along with inhibition of the interferon gamma pathway in mice.
Mok and Allison found that if you give anti-interferon gamma treatment at the same time as checkpoint immunotherapy, the former compromises the effectiveness of the latter, because it can upregulate immunosuppressive PD-L1 on dendritic cells, which are important immune cells necessary for T cell activation. Fortunately, when interferon gamma treatment was given after checkpoint immunotherapy, it could prevent subsequent PD-L1 expression, significantly delay tumor growth, and enable superior anti-tumor immune memory thought to be mediated by T cells.
One of the final sessions of this meeting was led by Dinah S. Singer, Ph.D., who provided an overview of how the National Cancer Institute has sought to adapt and respond to the COVID-19 pandemic. Singer stressed the importance of continuing cancer research even during this time and pointed to a variety of initiatives that have enabled the NCI to continue enrolling patients in clinical trials, not only for COVID-19 but also for a variety of cancer types.
Like a number of Cancer Research Institute scientists, researchers around the world, including at the NCI, have shifted the focus of their work to SARS-CoV-2 and lent their scientific expertise to collaborative efforts to confront the pandemic. In time, their collective efforts will hopefully enable us to blunt COVID-19’s impact by providing ways to prevent infection as well as treat severe disease.
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