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).
• In preclinical studies, KRAS G12C inhibition increased the activity of the anti-tumour immune response but failed to sensitise 'cold' tumours to immune checkpoint inhibition; clinical trials of KRAS G12C + PD-1 inhibition are on-going

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. 

• Preclinical studies suggest that a PIK3CA hotspot mutation (H1047L, pancancer prevalence 0.4% in GENIE v8) may be amendable to targeting by directed T cell therapy.

• Another setback for TIGIT as a therapeutic target with the phase 3 SKYSCRAPER-01 trial showing no benefit of adding TIGIT inhibition (tiragolumab) to PD-1 inhibition (atezolizumab) in previously untreated advanced NSCLC
• Whilst tumour mutational burden (TMB) from ctDNA predicted response to immunotherapy in NSCLC (ORR TMB high vs low, 36% vs 6%), numerically one third of responders are in the TMB low group. The search for useful biomarkers continues.

• Monalizumab, an inhibitor of the novel immune checkpoint NKG2A, has failed in a phase 3 study of head and neck cancer; studies in lung cancer are on-going.

• An analysis of published trials found no evidence for synergistic or additive effects when combining IO agents with other cancer therapies; rather, combinations offer patients more than one independent chance to respond.

• Recent paracetamol administration reduced the efficacy of immune checkpoint inhibition in preclinical models and patient cohorts; IL-10 production and increased Treg infiltration are implicated.

• Updated analysis of KEYNOTE-158 confirms efficacy of PD-1 inhibition for MSI+ tumours, with ORR endometrial 49%, small intestine 48%, ovarian 33%, gastric 31%, biliary tract 41%, pancreas 18%; overall median duration of response 48 months.
• A GITR-targeting mab was well tolerated and resulted in immune cell activation in a phase 1 study; however, single agent activity was poor (ORR 4%).
• A personalised cancer neoantigen vaccine has been successfully combined with chemo and PD-1 blockade in a phase 1b study in lung cancer; neoantigen-specific T cells were observed, as was epitope spreading to non-immunised antigens.

• Preclinical work describes the development of a T cell receptor that is able to specifically target HLA-bound KRAS G12D whilst sparing wild-type KRAS; 4.3% of all cancers harbour this mutation, including 37% of pancreatic cancers.

   

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. 

• Concerns have been raised around the reproducibility of Ki-67 IHC following the recent FDA approval of abemaciclib; this follows on from similar reproducibility problems with ERBB2 (HER2) and PD-L1 IHC (passim).

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.

• Whilst on-going studies are exploring enhancement of anti-tumour immunity by PI3K-delta inhibition, continuous dosing is hampered by immune-related adverse events. Preclinical studies suggest that intermittent dosing may be the answer

• Preclinical studies have identified ATR-induced upregulation of CD47 and PD-L1 expression as a mechanism of inhibiting an anti-tumour immune response following localised radiotherapy.

• From 2017-2021, the FDA approved 161 new oncology drugs, 26% of which were accelerated approvals; chemotherapy accounted for only 2.5%, small molecules for 39% (85% biomarker-dependent) and immunotherapy for 42%. Of the 42 accelerated oncology approvals, 8 succeeded and 5 failed in definitive trials; the remaining 29 are currently ‘hanging’.
• Two recent studies failed to show benefit of PARP inhibition in unselected patients with ovarian or bladder cancer but find efficacy in patients with homologous recombination pathway mutations in secondary analysis. Based on the biological mechanism of PARP inhibition, and the failure of multiple studies to show efficacy beyond HR deficient tumours, the basis for preforming clinical trials in unselected patients is questionable. Read more here and here 

• Of oncology drugs entering phase 1 clinical development in 2015, only 6% were approved for patient use by 2021. Higher chances of success were observed for monoclonal antibodies and drugs showing at least 40% response rate during phase 1.

• Of the 50 new drugs approved by the FDA in 2021, 66% were supported by human genetic evidence, highlighting the importance of human genetics in drug discovery.

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
• The addition of the BTK inhibitor ibrutinib to standard chemoimmunotherapy (bendamustine + rituximab) significantly improved PFS (81 versus 53 months) but did not improve survival, despite fewer progression-related deaths in the ibrutinib arm.
• The CAR T development pipeline is looking increasingly congested, with around 800 products in development for five haem cancers, of which over 300 are targeting acute lymphoblastic leukaemia; another case of 'me too' inefficiency?

• Genomic instability, detected by low pass whole genome sequencing, was a predictor of poor response to CD19 CAR T cell therapy in a retrospective study.

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.

   

EQUALITY

• In real-world US data, black patients with colorectal or lung cancer were significantly less likely to undergo biomarker testing than white patients; black patients with NSCLC were also less likely to be treated on a clinical trial (3.9% v 2.1%).

REGULATORY

• The debate around tightening up the FDA accelerated approval pathway continues; suggestions include requirements for sponsors to commence confirmatory trials prior to approval and automatic expiry of approvals if targets are not met.

BLADDER

• Real world data suggest that patients with tumour mutation burden ≥10 have more favourable outcomes with first line immunotherapy (PD-(L)1 inhibition) rather than chemotherapy.