AACR19 Day 4 Update: The Microbiome, Immunotherapy Biomarkers, and New Immune Targets

The more we learn about the immune system and cancer, the more we have also come to realize the important role bacteria in our gut play in influencing our body’s ability to fight cancer. The makeup of microorganisms in our body, called the microbiome, can enhance or diminish our immune system’s ability to prevent life-threatening cancers from arising in the first place or, in cases where cancer has developed, can influence clinical outcomes in patients treated with immunotherapy. Significant efforts are underway to better understand the ecosystem of the microbiome and its impact on our immune system, a primary goal of which is the development of preventive and therapeutic interventions that can lower cancer incidence and improve patient responses to treatment. The first major symposium of the day, titled, “The Microbiome as an Orchestrator of Immunity and Cancer Immunotherapy,” highlighted cutting-edge research into this important new area of inquiry.

CRI CLIP Investigator Gregory F. Sonnenberg, PhD, of Weill Cornell Medicine, kicked off the session with a look at the immune cells that are responsible for maintaining the proper functioning of our gastrointestinal (GI) tract. Sonnenberg began by discussing how interleukin-2 (IL-2), a signaling molecule of the immune system, helps regulate intestinal health by acting on regulatory T cells (Tregs), which then act to control killer T cell activity, noting that the loss of IL-2 leads to the entire GI tract becoming inflamed. Sonnenberg also noted that while the factors responsible for Treg activity in the large intestine have been well-studied, much less is known about the factors that induce their activity in the small intestine. Recently, however, Sonnenberg revealed the importance of immune cells known as innate lymphoid cells (ILCs) in intestinal homeostasis, including in the small intestine, and also found that they exhibited altered activity in patients with inflammatory bowel disease (IBD) as well as colorectal cancer (CRC), where they even appear to influence the type of tumor that develops.

Gregory F. Sonnenberg, PhD, of Weill Cornell Medicine, discusses the immune cells in the gastrointestinal tract.

Next, Giorgio Trinchieri, MD, a member of the CRI Scientific Advisory Council who works at the National Cancer Institute, discussed how the microbiome can influence patient responses to PD-1 checkpoint immunotherapy, citing studies from multiple institutions that revealed various bacterial species associated with responses in patients with melanoma, lung cancer, and kidney cancer. Interestingly, each of these trials—which were conducted in different locations—identified different bacteria associated with patient benefit. Even with respect to a bacterial species called Faecalibacterium prausnitzii that was shared by the different patient groups, patients possessed different strains, prompting Trinchieri to suggest a possible geographic bias. However, he noted that this phenomenon could allow for the identification of strain-specific genes and enable researchers to uncover clues regarding the molecular mechanisms responsible for bacteria-associated immunotherapy benefits.

Giorgio Trinchieri, MD,of the National Cancer Institute, discusses how the microbiome can influence patient responses to immunotherapy.

The goal now, Trinchieri proclaimed, must be to discover microbiome-related biomarkers that aid doctors in predicting which patients will respond in a location-agnostic fashion. He also stressed the need to identify favorable microbiome compositions that could then guide fecal microbiota transplants (FMTs) from either healthy donors or patients who’ve already responded to immunotherapy. Additional factors, such as certain diets, that enable favorable bacterial compositions to be induced or maintained after transplantation would also aid these efforts in the clinic. Along those lines, Trinchieri pointed to a trial at the University of Pittsburgh in which patients who initially didn’t respond to PD-1 immunotherapy were re-treated with immunotherapy after receiving FMTs from patients who did respond. Other trials underway, he noted, are supplying patients with defined bacterial compositions in order to induce a more favorable microbiome and hopefully improve the effectiveness of immunotherapy.

Turning to lung cancer, Solange Peters, MD, PhD, of the University of Lausanne (Switzerland), discussed the phase III MYSTIC trial in which patients with metastatic non-small cell lung cancer (mNSCLC) were treated with either chemotherapy, PD-L1 immunotherapy, or a combination of PD-L1 and CTLA-4 immunotherapies. Previously, high tumor mutational burden (TMB) has been shown to be predictive of survival in patients with mNSCLC. This work—which involved former CRI Clinical Team Leader Scott J. Antonia, MD, PhD, formerly of the Moffitt Cancer Center and now at Duke University, and was led by Columbia University’s Naiyer Rizvi, MD, PhD, who is currently leading a CRI-funded biomarker trial—focused on the value of determining TMB by measuring circulating tumor DNA in the blood, which can be done more rapidly and in a less invasive manner than by acquiring tissue from the tumor itself. This blood TMB (bTMB) might also better reflect the genetic variation of metastatic lesions. Overall, bTMB samples were obtained from more than 800 patients, with at least 250 patients from each of the treatment groups, which enables robust analysis.

Solange Peters, MD, PhD, of the University of Lausanne, discusses the phase III MYSTIC trial.

While there was little difference in survival between the different treatment groups when all patients were grouped together regardless of TMB, a significant survival benefit was observed in patients with bTMB values greater than 16 mutations / DNA Megabase (m/Mb). In these patients, 39% of those treated with the combination immunotherapy were alive after two years, compared to only 18% of those treated with chemotherapy. Furthermore, when the bTMB cutoff was raised to 20 m/Mb, the two-year survival rates were 48% versus 19%, for the combination immunotherapy- and chemotherapy-treated groups, respectively. The patients in this group who received combination immunotherapy also experienced significantly higher progression-free survival rates (39% versus 2%) at two years, and higher response rates (48% versus 21%). Overall, among patients with bTMB values greater than 20 m/Mb, those treated with the combination immunotherapy experienced a 51% reduction in risk of death and 47% reduction in risk of progression compared to those treated with chemotherapy, thus highlighting bTMB’s value as a predictive biomarker of benefit with immunotherapy. In general, these trends were also seen in patients treated only with PD-L1 immunotherapy, but to a lesser extent than those that received the combination. However, given that these high TMB patients represent a small fraction of the overall patient population, doctors should be wary about limiting this immunotherapy approach to only those patients, as those with low TMB can potentially still benefit too.

In another session, Hyun Cheol Chung, MD, PhD, of Yonsei University (South Korea), presented results from two trials—Keynote-028 and Keynote-158—using PD-1 immunotherapy as a third-line or later treatment for patients with advanced small cell lung cancer (SCLC). This work was led by Patrick Ott, MD, PhD, of the Dana-Farber Cancer Institute, who is leading a CRI-funded trial testing the same approach in patients with breast, ovarian, colorectal, cervical, and kidney cancer. Of the 83 patients evaluated, 16 had responses, equivalent to a 19% response rate, and another 15 had diseases stabilization. Six patients were not assessed post-treatment. Importantly, the median duration of response was not reached, and nine of the sixteen patients (61%) had responses that lasted at least a year and a half, showing that these immunotherapy-induced responses can be and often are durable. With respect to overall survival, the median overall survival was 7.7 months and 21% of patients were still alive at the two-year mark.

Hyun Cheol Chung, MD, PhD, of Yonsei University, presents results from  the Keynote-028 and Keynote-158 trials at AACR19.

Julius Strauss, MD, presented a study led by James Gulley, MD, PhD, his colleague at the National Cancer Institute, in patients with human papilloma virus (HPV)-associated cancers, of which there are more than 30,000 new cases in the United States—and more than 630,000 new cases globally—each year. In this trial, patients with refractory, HPV-associated cervical, anal, and head and neck cancers were treated with the M7824 bifunctional fusion protein that targets both the TGF-β and PD-L1 immunosuppressive pathways. Of the 43 patients treated, 36 were confirmed to have HPV-positive cancer. When taking into account patients who experienced pseudoprogression (apparent tumor growth that is actually the result of infiltration by lymphocytes) and had delayed responses, 35% of those with HPV-associated disease and 39% of those with HPV-positive disease responded. As of January, 73% of those responses were ongoing, with the longest still ongoing at more than two years, and responses were seen in both PD-L1-positive and PD-L1-negative disease. Additionally, at the one-year follow-up mark, 56% of those with HPV-associated cancer and 62% of those with HPV-positive cancer were still alive.

Julius Strauss, MD, of National Cancer Institute, presents a study in patients with HPV-associated cancers at AACR19.

With respect to biomarkers in liver cancer, CRI CLIP investigator Ignacio Melero, MD, PhD, of the University of Navarra and the Foundation for Applied Medical Research (Spain), presented results from a phase I/II trial of PD-1 checkpoint immunotherapy in hepatocellular carcinoma, the most common form of liver cancer. Melero revealed that increased tumor PD-L1 expression was associated with both responses and increased overall survival in liver cancer patients treated with PD-1 immunotherapy. Overall, 28% of the patients with PD-L1-positive tumors responded and had a median overall survival of 28 months. Additionally, patients whose tumors expressed markers associated with the T cell receptor were more likely to respond and showed a slight trend toward increased overall survival. The study also evaluated patients according to the inflammatory signature score (developed by Bristol-Myers Squibb), which looks at the expression of PD-L1, CD8A, LAG3, and STAT1. They found that the median inflammatory signature score was significantly higher in patients who responded to PD-1 immunotherapy compared to those who didn’t respond or had disease stabilization and correlated with improved overall survival.

Ignacio Melero, MD, PhD, presents results from a phase I/II trial of PD-1 checkpoint immunotherapy in hepatocellular carcinoma.

Roberta Zappasodi, PhD, of Memorial Sloan Kettering Cancer Center (MSKCC), explored strategies to target the GITR immune pathway with a drug called TRX518. This approach was first evaluated in a CRI-funded trial involving Zappasodi’s MSKCC colleagues Jedd D. Wolchok, MD, PhD, an assistant director of the CRI Scientific Advisory Council, and former CRI fellow Margaret Callahan, MD, PhD, as well as Case Western Reserve University’s Henry Koon, MD In this trial, they found this GITR-targeting approach led to decreased numbers of regulatory T cells (Tregs) in both the tumors and the peripheral blood of patients. Those insights provided a rationale for combining immunotherapies targeting the GITR and PD-1 pathways, and in preclinical experiments they found that this combination approach led to more activated and less exhausted killer T cells compared to either treatment alone. These killer T cells also exhibited enhanced cancer-killing capabilities, and as a result of this preclinical validation, a trial has since been launched to evaluate this combination of GITR and PD-1 immunotherapies in patients with advanced solid cancers.

Roberta Zappasodi, PhD, (MSKCC) discusses strategies to target the GITR immune pathway.

The day concluded with a “star-studded” plenary featuring pioneers in CTLA-4 blockade therapy discussing their work that led to the first FDA-approved checkpoint immunotherapy for cancer (ipilimumab, BMS) in 2011, which has since made possible numerous new therapeutic strategies in a variety of cancers. First among the presenters was MD Anderson Cancer Center’s James Allison, PhD, director of CRI’s Scientific Advisory Council who in 2018 received the Nobel Prize in Physiology or Medicine for his discovery of CTLA-4’s negative regulation of immune cell activation and his development of the first therapeutic intervention based on this idea (ipilimumab). Next was Jeffrey Bluestone, PhD, of the University of California, San Francisco, and the Parker Institute for Cancer Immunotherapy, whose study of the CTLA-4 and CD28 pathways and their potential as therapeutic targets in the control of autoimmunity, diabetes, and transplant rejection shed light on CTLA-4’s role in T cell regulation and immune tolerance, contributing to the development of CTLA-4 blockade as an effective cancer therapy. (Dr. Bluestone was honored this year with the AACR-Irving Weinstein Foundation Distinguished Lectureship for his many contributions to our understanding of T cell biology.) Alan Korman, PhD, of Bristol-Myers Squibb, spoke next about his work to move anti-CTLA-4 through drug development toward clinical trials. He did this work in collaboration with CRI Scientific Advisory Council member Nils Lonberg, PhD, first at the biopharmaceutical company Medarex, which developed the first fully human CTLA-4-blocking antibody, and later at BMS, after it acquired Medarex in 2009. Finally, Jedd D. Wolchok, MD, PhD, of MSKCC spoke about his role as a principal investigator on the registrational trials that led to FDA approval of ipilimumab and the vital work he and co-investigators did along with the ipilimumab team at BMS to develop meaningful patient response evaluation criteria that could accurately demonstrate to federal regulators the drug’s effectiveness in treating patients with metastatic melanoma. Fortunately for cancer patients everywhere, they succeeded, setting the stage for the many immunotherapy approvals that have since brought these lifesaving treatments to patients in a variety of cancer types.

Drs. James Allison and Jedd Wolchok, two pioneers in CTLA-4 blockade therapy.

That’s it for Day 4 from AACR19! Check back on our blog tomorrow for our recap of the Day 5 here in Atlanta!