Weekly Immune Digest

As an introduction to this new topic on our website, we will select relevant articles in the immunotherapy and immune-biomarker field, just for your interest and on a weekly basis.

If you want us to add here your achievement in these domains, just email us and Philip Beer  with one sentence on your manuscript and the correct reference.

At your service!

LUNG

• Spatial analysis of tumour infiltrating T cells using artificial intelligence predicted response to immune checkpoint inhibition in advanced NSCLC.
• In early stage NSCLC, the addition of PD-1 inhibition (nivolumab) to neoadjuvant chemotherapy improved pathological CR at surgery (24% versus 2%) and extended event free survival (32 versus 21 months).

COLORECTAL

• In a single arm study, temozolomide priming followed by combined PD-1/CTLA-4 inhibition (ipilimumab + nivolumab) delivered ORR 45% in previously treated, MGMT promoter methylated, microsatellite stable, advanced disease.

PROSTATE

• In a retrospective analysis of patients with mCRPC, immune checkpoint inhibition was more effective than taxane chemotherapy for the 6% of patients with tumour mutation burden >10 mutations/Mb, otherwise taxanes were more effective.
• A phase 3 study of combined PD-1 and PARP inhibition (pembrolizumab + olaparib) has been terminated due to lack of efficacy; the trial did not preselect patients with PARP-sensitising HR gene mutations.

IMMUNOTHERAPY

• A window study in ovarian cancer sheds light on the failure of IDO1 inhibitors in clinical trials: metabolic rewiring of the immune microenvironment in IDO1 inhibitor exposed tumours resulted in bypass suppression of T cell activity.
• The US-based NCI-MATCH study has opened a new arm to study combined inhibition of PD-1 and LAG-3 in patients with microsatellite unstable tumours who have failed anti-PD-(L)1 therapy.
• The FDA have approved combined PD-1/LAG-3 inhibition in advanced melanoma, based on improved PFS versus PD-1 inhibition alone in the RELATIVITY-047 phase 3 trial.
• European regulator CHMP has taken a more conservation view than the FDA to pembrolizumab (anti-PD1) in microsatellite unstable disease, restricting its recommendation to MSI+ colorectal, endometrial, gastric, small bowel & biliary cancers.
• A new study based on five melanoma cohorts uncovers complexity in the role of the gut microbiome in predicting response to immune checkpoint inhibition, with cohort-dependent effects complicating response prediction.
• The TIGIT inhibitor tiragolumab failed to improve outcomes in SCLC when combined with PD-L1 inhibition and chemotherapy in the phase 3 SKYSCRAPER-02 study.
• There are currently at least 33 different PD-1/PD-L1 antibodies in clinical development, with similar, if not identical, mechanisms of action and safety profiles.
• In a retrospective study of patients with CAR T treated B cell lymphoma, recent antibiotic use was associated with worse outcomes and increased neurotoxicity; prospective analysis linked outcomes to specific gut bacterial taxa.
• A live bacterial culture designed to enhance the growth of gut bifidobacterium improved PFS in response to combined PD-1/CTLA-4 inhibition in a small randomised phase 1 study of metastatic renal cancer.

• A new clinical trial will genetically modify tumour infiltrating T cells (TILs) from patients in order to block PD-1 expression and (hopefully) enhance T cell responses; the trial will be open to patients with advanced melanoma or NSCLC.

BREAST

• Excellent 15-years outcome in systemically untreated young (<40 years old) patients with triple negative breast cancer, but only when these patients have a high number of TILs.
• ASCO have updated treatment guidelines to recommend the use of neoadjuvant and adjuvant PD-1 inhibition (alongside standard therapy) for patients with high risk early stage triple negative disease.

CLINICAL TRIALS

• The number of cancer patients taking part in clinical trials has doubled over the last decade; hopefully this trend will continue. IQVIA Global Trends in R&D 2022
• Only 5% of oncology drugs entering phase 1 development achieve regulatory approval; the probability of success is higher for rare tumours/subtype (16%) compared with common tumours (1%). IQVIA Global Trends in R&D 2022

BRAIN

• In preclinical models, IL-10 release from myeloid cells drives a T cell exhaustion phenotype and contributes to the immunosuppressive state that is typical of glioblastoma.

MELANOMA

• The IL2/PD-1 combo bempegaldesleukin + nivolumab failed to meet any endpoints in a pivotal phase 3 trial for patients with advanced disease.
• Using imaging mass cytometry, a study of patient samples identified the proximity of proliferating antigen-experienced cytotoxic T cells to melanoma cells in pre-treatment biopsies as predictive of response to immune checkpoint inhibition.

DRUG TARGETS

• Despite efficacy in treating B cell cancers, PI3K-delta inhibitors may reduce overall survival due to toxicity; a recent FDA review will likely impact future drug development, including a move away from approval based on single arm trials.

• BTK inhibitors can induce autoimmunity when used to treat blood cancers; analysis of on-treatment patient samples identified selective Treg reduction, an effect which could potentially be used to enhance anti-tumour immunity.

   

HAEMATOLOGICAL

• CD19 CAR T therapy showed promising efficacy with manageable tolerability when administered first line to patients with high risk diffuse large B cell lymphoma; objective response rate 89% with 78% complete response

CELL THERAPIES

• CD4/CD8-negative CAR T cells showed efficacy against CD19+ leukaemia in preclinical xenograft models without inducing graft versus host disease, raising hopes that double negative T cells may be used to generate allogenic CAR T therapy.