Immune to Cancer: The CRI Blog




ASCO 2022 Recap: Cancer Immunotherapy Updates

Since the first FDA approval in 2011 to treat cancer patients with checkpoint immunotherapy, doctors have sought to understand not only why some patients respond but also how to help those who don’t.

The 2022 annual meeting of the American Society of Clinical Oncology (ASCO22) showcased new studies and data that demonstrate great progress in both regards, thanks to new technologies and the increased attention to immunological monitoring that’s become central to many trials. Most importantly, new insights offer the potential to expand immunotherapy’s benefits to more people, including those with rare cancers.

At the heart of this clinical discovery are biomarkers, which shed light on what’s going on within patients. Biomarkers can relate to tumor mutations, immune cell numbers, or a host of other biological characteristics. The right biomarkers can enable doctors to pair people with the therapies most likely to work for them.

For example, high microsatellite instability, or MSI-high, is a biomarker indicating that a tumor’s genome has become unstable and heavily mutated. In a phase I trial involving MSI-high patients with stage 2-3 colorectal cancer, PD-1 checkpoint immunotherapy (dostarlimab) completely cleared the tumors in the first 14 people treated. The plan was to use chemotherapy and surgery in those who didn’t respond, but so far no one has needed it, nor have any of the patients experienced recurrence. The MSI-high biomarker also proved useful with PD-L1 checkpoint inhibition (atezolizumab) in cancers of the stomach and gastroesophageal junction, where a phase 2 trial linked the trait with improved tumor responses prior to surgery.

MSI-high is valuable due to its high predictive power, and was the first biomarker incorporated into an immunotherapy approval for all cancer types, regardless of origin. But it’s also relatively uncommon. Roughly 10 percent of colorectal cancers are MSI-high, but only 3-4 percent of all cancers.

Other biomarkers will need to be considered to guide immune-based treatments for the vast majority of patients. An approach called Immunoscore uses killer (CD8+) T cell infiltration and PD-L1 expression to categorize and sort tumors based on immune status. In a retrospective lung cancer study involving PD-1/PD-L1 immunotherapy, all the patients with low immunoscores relapsed within 45 days, whereas only a third of those with high immunoscores relapsed within three years — a powerful predictor of individual cancer patient outcomes.

Likewise, VIGex uses 12 genes related to immune activation and suppression to categorize tumors into hot, intermediate, or cold — terms describing how readily the immune system sees and attacks tumors, hot being the most likely to trigger an immune response and cold the least. These signatures were predictive of benefit in patients treated with PD-1 immunotherapy (pembrolizumab) in the phase 2 INSPIRE trial, including in forms like triple-negative breast cancer and sarcoma that don’t typically respond to immunotherapy. Importantly, combining VIGex with measurements of circulating tumor DNA (ctDNA) further improved the platform’s predictive power.

Dr. Lacey Padrón discusses the PRINCE pancreatic cancer trial.

In the Cancer Research Institute’s PRINCE pancreatic cancer trial, patients with metastatic disease were treated with various combinations of chemotherapy, PD-1 immunotherapy (nivolumab), and a novel drug (sotigalimab) that stimulates the CD40 pathway on antigen-presenting immune cells. Through deep immune profiling that involved samples taken both before and after treatment, researchers identified immune-related signatures in both the blood and tumors that were associated with responses to two immunotherapy combinations.

As described by Lacey Padrón, PhD, of the Parker Institute for Cancer Immunotherapy, CRI’s clinical research partner on the PRINCE study, pancreatic cancer patients who responded to treatment with PD-1 therapy plus chemotherapy also had higher pre-treatment levels of activated immune cells including effector memory T cells and follicular helper T cells in the blood, while the number of circulating mature helper T cells, B cells, and dendritic cells were associated with those who responded to CD40 therapy plus chemotherapy. Patients who benefited from the first combo also had fewer signs of immunosuppressive activity within tumors, whereas the latter had tumors more heavily infiltrated by non-proliferating helper T cells. Further studies are needed to confirm the predictive power of these biomarkers.

A study of patients with melanoma, lung cancer, and sarcoma, another less common tumor type, highlighted how the composition of one’s bacterial microbiome, particularly in their intestine, can affect patient responses. Analysis of patients’ stool before treatment demonstrated a connection between the presence of certain types of microbes, the formation of tertiary lymphoid structures (TLS) and activated B cells after treatment, and major responses in patients treated with the combination PD-1 (nivolumab) and CTLA-4 (ipilimumab) blockade.

Dr. Laurence Albiges highlights the MEDI5752 bispecific checkpoint immunotherapy.

On the subject of dual PD-1 and CTLA-4 immunotherapy, Laurence Albiges, MD, PhD, of Gustave Roussy Institute (France), described studies of a promising new bispecific antibody (MEDI5752) that targets both checkpoint targets. In a phase I trial for people with advanced kidney cancer, this two-checkpoints-one-molecule strategy led to deep and durable responses in many patients, and offered benefits in terms of dosage compared to traditional combination strategies using separate PD-1- and CTLA-4-targeting drugs. Another similar PD-1 and CTLA-4 bispecific (AK-104) led to remarkable response and survival rates when used as a first-line treatment in combination with a VEGFR-targeting drug (bevacizumab) in a phase 2 trial for patients with recurrent and metastatic cervical cancer.

Another innovative approach to overcoming resistance to checkpoint immunotherapy was showcased in the phase 1/2 ARTISTRY-1 trial, the first to test an engineered IL-2 cytokine (nemvaleukin alfa) designed to stimulate killer T cells but not immune-suppressing regulatory T cells (Tregs). This therapy boosted the expansion of anti-tumor T cells and natural killer cells, but not Tregs. When combined with PD-1 therapy (pembrolizumab), proved capable of inducing responses in heavily pre-treated patients, even after prior PD-1 therapy., according to Ulka Vaishampayan, MD, of the University of Michigan Cancer Center.

Dr. Ulka Vaishampaya presenting results from the ARTISTRY-1 study.

Glioblastoma (GBM), an aggressive form of brain cancer, is considered one of hardest cancers to treat, including with current checkpoint immunotherapies. Here too, though, bacteria were found to be an important predictor of longer survival that may help identify those who, albeit still in the minority, can benefit from existing treatments—in this case, newly diagnosed glioblastoma patients who were treated with PD-L1 therapy (atezolizumab) plus chemotherapy and radiation.

David Reardon, MD, highlighted another trial for patients with newly diagnosed glioblastoma, where survival after treatment with a combination of PD-1 therapy (cemiplimab) and tumor-targeting and immune boosting vaccines was associated with blood biomarkers indicating the presence of activated T cells.

Dr. David Reardon speaks about an immunotherapy combination in glioblastoma.

The patient experience is also an important and increasingly appreciated measure of response as well as a predictor of long-term benefit, as evidenced by the incorporation of patient-reported outcomes (PROs) and health-related quality of life (HRQoL) biomarkers in large phase 3 immunotherapy studies like CheckMate 214 in kidney cancer, HIMALAYA in unresectable liver cancer, and TOPAZ-1 in rare advanced bilary tract cancers. Of particular promise, patients with higher HRQoL scores and better PROs tended to survive longer in the CheckMate-214 and TOPAZ-1 studies, respectively.

By taking into account the full picture of patient responses to immunotherapy – understanding how their immune system is responding at a molecular and genetic level and looking not only at how the patient appears to be doing based on scans but also accounting for patient-reported quality-of-life improvements – doctors and scientists are discovering new and important signals that help to guide personalized treatment decisions that are more likely to help each patient. For patients with rare cancers that often are not directly studied within clinical trials, the presence of predictive biomarkers like those discussed at #ASCO22 may lead to regulatory approvals that would cover patients with rare cancers who have one or more of these biomarkers.

Other immunotherapy successes were hailed at #ASCO22, including groundbreaking results from the DESTINY-Breast04 study showing the dramatic improvement to overall patient survival in HER2 negative breast cancer patients treated with Enhertu, an antibody-drug conjugate. Treatment more than doubled survival in patients with this historically deadly form of breast cancer compared to patients who received standard chemotherapy alone, regardless of hormone receptor (HR) status. News of this progress was met with a standing ovation by thousands of conference attendees.

Immunotherapy has transformed the treatment of many cancers since the first approval in 2011 of checkpoint blockade therapy. While immunotherapy currently works in roughly a quarter of patients treated, researchers around the world today are actively developing effective new strategies based in individual biology that not only promise to help those with the most common cancers, but also help some patients with rare and understudied forms of cancer. Through continued study of the immune system and cancer and identification of biomarkers to help predict treatment outcomes, doctors are poised to provide patients with a menu of treatment options most likely to benefit them, no matter the type of cancer they have or how rare it might be.

Photos by Arthur Brodsky.

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