The Immunotherapy 360 blog space features articles that encompass prominent issues related to immunotherapy. These are written with the assistance of the staff at AIM at Melanoma, AIM with Immunotherapy and health care practitioners.
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Genetics Define Biomarkers of Response to Immunotherapy
Immune checkpoint inhibitor (ICI) therapy, such as nivolumab, pembrolizumab, atezolizumab or combinations with ipilimumab, can be extremely impactful for treating cancer patients, but it is not without limitations. ICIs elicit immune-related adverse events and unfortunately, they do not work for every patient. Some patients treated with ICIs will not respond.
A recent study published in Nature Genetics aimed to identify genetic biomarkers that could distinguish ICI-responders from non-responders. Using an unbiased genetic approach, the investigators analyzed genomic and transcriptomic data among treated patients to differentiate factors representing ICI-responders versus non-responders. Their analysis revealed five latent factors: three are associated with ICI response, and two reflect tumor, microenvironment, and host factors that influence patient survival.
Three latent factors associated with ICI response:
- Tumor Mutation Burden – among the genetic results obtained, the single feature with the highest correlation overall was tumor mutation burden. An increase in tumor mutation burden is associated with a higher probability of response to ICIs and an increase in survival.
- Prior Treatment – prior exposure to systemic therapy and prior exposure to any therapy are negatively associated with ICI response and survival. The rationale for this is an increase in tumor aggression and/or a decline in the patient’s condition.
- T cell Effective Infiltration – based on the gene expression of the cluster identified, effective T cell infiltration appears to be critical. An increase in T cell infiltration into the tumor is associated with a higher probability of a response to ICIs and longer patient survival.
Two latent factors that influence the survival of patients:
- Transforming Growth Factor-Beta Activity in the Microenvironment – the highest correlation between genes in a defining gene cluster showed TGF-β activity in fibroblasts. Low values of TGF-β activity in the microenvironment are associated with longer survival of patients treated with ICIs. Therefore, TGF-β activity in this context has a negative association with response and survival.
- Tumor Proliferative Potential – a group of genes from the tumor clustered with other genes sets representing cell cycle and cell proliferation and it was dubbed ‘Proliferation Potential.’ In this set and the validation cohorts that had transcriptomic data available, tumor proliferative potential was negatively associated with survival among patients.
How did researchers uncover these biomarkers?
Among the 5,288 samples in the Hartwig Medical Foundation, researchers used 479 patients with metastatic cancer who received ICI therapy and had survival information available. Among these, 191 were diagnosed with melanoma, 110 with lung cancer, 88 with bladder cancer, and the remaining 90 with other cancer types. The whole transcriptome was sequenced for 396 of these samples.
Using these samples, the following features were collected: single nucleotide variants, base insertions or deletions in the genome, copy number status of 2,415 genomic regions, somatic mutation features of the tumor, whether known driver variants occurred, and genomic instability. Other features included were the clinical characteristics of the tumor, gene expression, metastatic features, and features affecting the immune response to the cancer.
Did the authors validate independent cohorts of other tumor types?
Yes, the authors validated the five latent factors in independent cohorts of the same and other tumor types. These cohorts included INSPIRE, Lyon, MARI-ATHASAN, PARKER ICI, RAVI, and VHIO. In total, 1,491 patients with metastatic tumors were used to validate their findings.
Why does this study matter?
Having biomarkers to identify patients with a low probability of responding to ICI therapy would help rapidly move them to another option with a chance for an improved outcome. Avoiding ICIs would also spare these patients from the potential of immune-related adverse events. Importantly, avoiding a likely unsuccessful therapy can help reduce the financial burden of providers and patients.
The possibility of identifying patients with tumors not usually amenable to ICI therapy but whose genetics indicate a high probability of response to ICIs is intriguing. The authors in this study applied their analysis to patients in their original cohort who did not receive ICIs. The results identified a fraction of patients with skin (35%), bladder (42%), and lung (16%) tumors that showed a high likelihood of response to ICIs. In addition, 4% of patients with breast cancer, 3% of patients with colorectal cancer, 19% of patients with renal cancer, and 15% of patients with liver cancer also showed a high probability of response to ICIs, even though these patients were previously considered not candidates for ICIs.
Although the scientific findings are far from ready for clinical incorporation, the work provides a frame of reference for biomarkers that indicate a high likelihood of a positive response to ICI therapy. Having biomarkers is especially important as certain ICIs have more than 40 indications for a single drug in at least 20 different types of tumors. Therefore, the potential of ICIs to treat other cancer types could be increased with information to differentiate responders from non-responders.
Reference:
This summary was based on the article by Usset J, Huber AR, Andrianova MA et al. Five latent factors underlie response to immunotherapy. Nat Genet. 2024;56(10):2112-2120. doi: 10.1038/s41588-024-01899-0.
Limits of Success Shown for the Combination of Ipilimumab with Nivolumab
Immunotherapy is a resounding success for the treatment of many cancer types, including those malignancies which previously had no reliable therapy to offer patients such as cutaneous (skin) melanoma. This success was the reason that an international study conducted an investigation on whether combination ipilimumab (Yervoy) and nivolumab (Opdivo) could offer a survival benefit to patients with acral melanoma. Unfortunately, the treatment had little impact.
Acral melanoma is a rare melanoma subtype that primarily occurs on the palms of the hands, soles of the feet, or the nailbeds—the non-hair-bearing surfaces of the body. Acral is biologically distinct from cutaneous melanoma, is thought to develop after significant injury or trauma to an area, and has a worse prognosis in comparison. Current guidelines do not always distinguish acral from cutaneous melanoma, which is problematic.
Since immunotherapy is therapeutic for many types of cancer, an international cohort of investigators conducted a retrospective analysis on acral melanoma. The current study examined the efficacy of combination immunotherapy with ipilimumab and nivolumab in 109 patients with Stage III (25.7%) and Stage IV (74.3%) disease.
Despite success with cutaneous melanoma, only 18.4% of patients (n=20/109) with acral melanoma responded to therapy, including 8.3% (n=9) with complete responses and 10.1% (n=11) with partial responses. Twenty-two patients (20.2%) had stable disease and the disease control rate was 38.5%.
In comparison, the CheckMate-067 study investigating PD-1/CTLA-4 inhibition in patients with cutaneous melanoma showed an overall response rate of 57.6%. This study’s overall response rate for patients with acral melanoma treated with PD-1/CTLA-4 inhibition was 18.3%.
The current study contained 73.4% (80/109) of patients who progressed with acral melanoma despite the combination of ipilimumab and nivolumab. Among the patients, 87.2% (n=95) experienced low-grade toxicities related to treatment, which was most commonly fatigue (30.3%), rash (22.9%), and pruritus (14.7%). Among the higher-grade toxicities, 40.4% (n=44) experienced grade 3-4 effects, which included colitis and hepatitis.
Overall, the results of the retrospective analysis’s results for acral melanoma were disappointing, given that ipilimumab plus nivolumab yields very good outcomes for advanced cutaneous melanoma. Recent clinical trial results demonstrated that 43% of patients with advanced cutaneous melanoma survived 10 years after their diagnosis when treated with ipilimumab plus nivolumab.
Although ipilimumab and nivolumab are approved in combination for at least seven other types of cancer, an insufficient number of patients with acral melanoma were included in previous clinical trials to definitively understand whether efficacy existed.
Several reasons are attributed to the reduced number of acral patients in trials, including the scarcity of patients with acral melanoma, the availability of the cohort to enroll in a trial, and the exclusion of acral in trials specific to cutaneous melanoma. Nevertheless, the lack of clinical trials for patients with acral melanoma left a gap in understanding whether immunotherapy might be therapeutic for acral, too.
Ongoing clinical trials for acral melanoma examine other potential efficacy options, such as triplet combinations with doublet PD-1 inhibitors, temozolomide, or VEGF inhibitors. The study authors cite the lack of immune recognition and lack of tumor-infiltrating lymphocytes within acral melanoma as major reasons for the failure of PD-1/CTLA-4 inhibitors.
Reference:
This summary is based on the publication “Combined PD-1 and CTLA-4 Blockade in an International Cohort of Patients with Acral Lentiginous Melanoma” in The British Journal of Dermatology by Erin McGillivray, Karam Ashouri, Eftychia Chatziioannou, et al. on October 23, 2024. DOI: 10.1093/bjd/ljae401
Colitis – A Common but Serious Adverse Event
Immune-related adverse events (irAEs) are unintended consequences of immunotherapies used in cancer treatment. Side effects can range from mild to very serious, and health care providers cannot yet predict who will suffer more side effects than others. Serious side effects can cause patients to interrupt or discontinue treatment, so managing them is a critical piece of treatment continuation. In the case of colitis induced by ipilimumab, patients may be retreated with immunotherapy under certain conditions.
What is colitis?
Colitis is an inflammation of the gastrointestinal lining. It is among the most common side effects observed in patients receiving immunotherapy or immune checkpoint inhibitors, especially CTLA-4 inhibitors, such as ipilumimab (Yervoy). In fact, 30-45% of patients receiving CTLA-4 inhibitors will experience some level of colitis. Patients with inflammatory bowel disease have an increased risk for developing colitis. Colitis is cited as a frequent reason for treatment interruption and discontinuation.
Inflammation in the gastrointestinal lining can cause bloating, cramping, diarrhea, and pain in the abdomen. Excessive watery diarrhea is a symptom of colitis (albeit not definitive, due to multiple other causes of diarrhea) that can indicate when a patient might be developing colitis. Moderate watery diarrhea, increasing to more than five loose bowel movements per day, usually arises five to ten weeks after immunotherapy begins, or after the second to third dose of immunotherapy.
What are the risks of colitis?
Although colitis can be a serious and potentially life-threatening complication, most patients will not have colitis that develops into a more serious condition requiring immediate intervention. Less than 11% of patients treated with single-agent ipilimumab or combination regimens containing ipilimumab will develop severe colitis. Infrequent but possible complications arising from serious colitis include bowel perforation, dehydration, hospitalization, sepsis, and shock. Mortality from gastrointestinal adverse events associated with response to ipilimumab is rare.
What are symptoms of a patient presenting with colitis?
The health care team may observe any of the symptoms listed below. Immune-related diarrhea is likely to impact most patients. However, diarrhea related to immunotherapy-associated colitis can also present in combination with upper gastrointestinal toxicity, enteritis, gastroenteritis, and gastritis.
- Mild to moderate symptoms: Abdominal pain, an increase of 4-6 stools per day, and blood or mucus in stool
- Serious symptoms: An increase of 7 or more stools per day, decreased appetite, fever, rapid change in gastrointestinal function, severe cramping and persistent abdominal pain Emergency symptoms: Shock, distress, and abnormal or unstable blood pressure
Why does colitis occur?
Immunotherapy is designed to supercharge the immune system. Unfortunately, the gastrointestinal tract can become susceptible to an immune system-provoked injury as an unintended consequence. Although immunotherapy is created with targeted properties aimed at the tumor’s environment, sometimes it non-specifically activates too much of the immune system throughout the body.
Nearly every organ system in the body is at risk for an unprovoked injury by ipilimumab. However, immunotherapy, particularly immune-checkpoint inhibitors in combination with ipilimumab, works so well in many patients that the risk of side effects is deemed worthwhile to achieve the possible results. Prompt and thorough communication about side effects by patients with their medical team allows for appropriate clinical support, and these two together allow immunotherapy to be used safely and successfully in many patients.
What can a clinician do for colitis?
Rapid identification and treatment can reduce the risk of progression from mild colitis. One of the first steps is to exclude infectious causes of diarrhea before treating ipilimumab-induced colitis. For patients treated with ipilimumab, colitis may rapidly progress within a period of days.
Practice guidelines recommend immunosuppression, usually with moderate to high doses of systemic corticosteroids. However, high-dose corticosteroid use is associated with other complications, such as tumor growth or an increase of infection. Prompt management of colitis can avoid drug interruption or discontinuation and allow a patient to remain on therapy.
Once a definitive diagnosis is made, supportive hydration, along with drugs such as loperamide, diphenoxylate/atropine, or a slow steroid taper may be given. Usually, the administration of high-dose systemic glucocorticoids in doses of 0.5-2 mg/kg prednisone equivalent daily is effective. Severe colitis may require intravenous steroids, such as budesonide, infliximab, or vedolizumab.
Where can I find more information on your website?
[New link to Aim with Immunotherapy’s ipilimumab – HCP toolkit; PAP; CSP for colitis] [New link to Aim with Immunotherapy’s ipi/nivo – HCP toolkit; PAP]References:
Dougan M, Wang Y, Rubio-Tapia A et al. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi: 10.1053/j.gastro.2020.08.063.
Frey C and Etminan M. Adverse Events of PD-1, PD-L1, CTLA-4, and LAG-3 Immune Checkpoint Inhibitors: An Analysis of the FDA Adverse Events Database. Antibodies (Basel). 2024;13(3):59. doi: 10.3390/antib13030059.
Ho C and Samlowski W. Outcome of an Accelerated Treatment Algorithm for Patients Developing Diarrhea as a Complication of Ipilimumab-Based Cancer Immunotherapy in a Community Practice.
Curr Oncol. 2024;31(6):3529-3545. doi: 10.3390/curroncol31060260.
Machado AP, Shaikh AS, Saji A et al. Outcomes of Budesonide as a Treatment Option for Immune Checkpoint Inhibitor-Related Colitis in Patients with Cancer. Cancers (Basel). 2024;16(10):1919. doi: 10.3390/cancers16101919.
Magahis PT, Corso T, Livingstone P et al. Open-capsule budesonide for the treatment of immune-related enteritis from checkpoint inhibitors. J Immunother Cancer. 2024;12(7):e009051. doi: 10.1136/jitc-2024-009051.
Oliveira C, Mainoli B, Duarte GS et al. Immune‑related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta‑analysis. Eur J Clin Pharmacol. 2024;80(5):677-684. doi: 10.1007/s00228-024-03647-z.