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

• The addition of either an anti-CD73 or anti-NKG2A monoclonal antibody to PD-L1 inhibition improved PSF compared with PD-L1 inhibition alone for patients with advanced NSCLC in the post chemo maintenance setting.

• A multimodal algorithm comprising radiology, histology and genomics was able to predict response to immunotherapy for patients with advanced NSCLC (AUC 0.80) with improved performance versus TMB (AUC 0.61) and PD-L1 (AUC 0.73).

• Preclinical studies and analysis of patient tumour material have identified a potential link between KRAS mutation and upregulation of tumour CD47 expression, mediated by PI3K signalling and resulting in immune evasion.

• First line chemo-free immunotherapy treatment has delivered clinically meaningful improvements in 5 year survival rates, irrespective of PDL1 status or histology (adeno vs squamous).

• The novel AXL inhibitor bemcentinib will be studied in combination with chemo and PD1 inhibition as first line therapy for STK11 mutant advanced NSCLC; loss of function STK11 mutations have been associated with increased AXL expression.

   

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.

• STING agonists delivered convincing preclinical efficacy but results have largely failed to translate; new preclinical work suggests that parallel inhibition of IL-35 may be required to unlock the therapeutic potential of STING activation.

• A trial of a novel approach to immunotherapy (NEON-2) combining a PDL1-dependent CD28 costimulator (davoceticept) with a PD1 inhibitor (pembrolizumab) has been abandoned following two early deaths from cardiogeneic shock.

• In a small feasibility study, personalised CAR T cells were generated against neoantigens for patients with refractory solid tumours; although CAR T cells expanded and infiltrated the tumours, stable disease was the best response.

• iPS-derived quadruple engineered allogeneic NK cells showed efficacy in preclinical models of myeloma; the cell product harboured a BCMA CAR, CD16 and membrane bound IL15 with CD38 knockout.

• Estimates of tumour aneuploidy, calculated from clinical targeted sequencing, can improve predictions of response to IO; patients with TMB low, aneuploidy high tumours show particularly poor responses to IO agents.

• In preclinical models, DHODH inhibition (brequinar) suppressed the development of myeloid-derived suppressor cells, thus enhancing the anti-tumour immune response; DHODH inhibition also augmented response to PD1 inhibition.

• The EU has approved the first allogeneic T cell immunotherapy product; tabelecleucel will be available to treat EBV-driven lymphoproliferative disease arising after haematological or solid tumour transplantation.

• Germline variation in cytokines including IL7 and IL22RA1 has been implicated in response to immune checkpoint inhibition as well as immune-related side effects.

• Structural variants targeting the PDL1 and PDL2 loci result in increased gene expression and identify tumours more likely to respond to PD1 inhibition.

• In preclinical solid tumour mouse models, locally applied CAR T cells (embedded in fibrin gel) improved survival following incomplete surgical resection of tumours; importantly, on-target off-tumour toxicity was diminished.

• A phase 1 trial of MAGE-A4 directed CAR T cells in expressing cancers reported ORR 24%; all patients experienced grade 3 or higher haematological toxicity; cytokine release syndrome was common but generally grade 2 or less.

• Two reports identify noncanonical splice junctions between coding exons and transposable elements as targetable tumour-specific neoantigens, potentially driven by altered epigenetic regulation.

• A genomic study of cancer samples has highlighted mutation and focal loss of heterozygosity of class 1 MHC as a frequent mechanism of tumour immune escape.

• A novel bispecific antibody targeting claudin 18.2 (CLDN18.2) and CD47 is entering clinical development; claudin 18.2 is overexpressed by pancreatic and gastric cancers.

• Mechanisms by which gut microbiota augment response to checkpoint inhibition (CPI) are unclear; a preclinical animal model implicates CPI-induced translocation of gut bacteria to lymph nodes and tumours with consequent immune activation.

• In patient tumours, dN/dS ratios specific for the immunopeptidome (i.e. genes encoding peptides that can be presented by HLA) identified immune edited tumours as resistant to PD(L)1 inhibition whereas immune-escaped tumours derived benefit.

• A phase 1 study demonstrated the feasibility of treating patients with autologous T cells engineered to express neoantigen-directed receptors using non-viral precision genome editing (CRISPR–Cas9 by electroporation).

• In preclinical models, commensal skin bacteria engineered to express tumour neoantigens elicited anti-tumour immune response following skin inoculation.

• In a pooled analysis of three NSCLC trials, patients experiencing mild to moderate immune related adverse events achieved longer overall survival compared with patients without.

• In a retrospective study, mutation of genes encoding the SWI/SNF complex was associated with favourable response to immune checkpoint inhibition across multiple cancer types.

   

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).

• The addition of PDL1 inhibition (durvalumab) to neoadjuvant chemotherapy improved overall survival in early stage triple negative disease, despite having only a small effect on the rate of pathological complete remission.

• In a meta-analysis of adjuvant trials of ERBB2-directed therapy, pathological complete remission (pCR) showed poor correlation with EFS and OS, casting doubt on pCR as a surrogate for early drug approval.

• In an exploratory analysis, response to PD1 inhibition (pembrolizumab) in advanced triple negative disease was associated with PDL1 expression, tumour mutational burden, tumour infiltrating lymphocytes and an inflamed T cell gene expression profile

   

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

• The FDA  is considering an overhaul of the oncology accelerated approval pathway; the central recommendation is for a single randomised trial, with accelerated approval based on ORR and full approval based on PFS/OS once data are mature.

• An analysis of confirmatory trials for drugs granted FDA accelerated approved found that half of all trials were not completed within the agreed time frame.

   

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.

• Preclinical studies have demonstrated efficacy for a T cell bispecific antibody directed against the brain tumour specific EGFRvIII; hopefully clinical studies will follow.

   

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.

• Immunotherapy with combination nivolumab/ipilimumab was superior to dabrafenib/trametinib in a phase 3 study of advanced BRAF V600-mutant disease.

• In a phase 3 trial, adoptive cell therapy with tumour-infiltrating lymphocytes improved survival compared with CTLA-4 inhibition (ipilimumab) for patients with advanced, PD1 inhibitor refractory disease.

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.

• A CAR T cell therapy trial will open shortly targeting delta-like ligand 3 (DLL3), an inhibitory NOTCH ligand, in SCLC and other neuroendocrine tumours.

• A new study to open soon in the UK (DETERMINE) will use genomic analysis to guide therapy selection for patients with rare cancers.

• A hyper-transcriptional state is common in cancer and is associated with worse clinical outcomes; hyper-transcription may also be a biomarker of response to immunotherapy with checkpoint inhibitors.

• Two recent phase 3 studies have indicated positive results for adding a claudin 18.2 targeted monoclonal antibody (zolbetuximab ) to chemotherapy in defined patient populations; full details to follow.

• A novel HDAC1 inhibitor will enter the clinical shortly in combination with PD1 inhibition for the treatment of STK11-mutant cancers, based on preclinical data linking STK11 loss with HDAC1/CoREST mediated resistance to immunotherapy.

   

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.

• A new target has entered clinical development in myeloma; GPRC5D CAR T cell therapy delivered 71% ORR in a phase 1 study, including responses in patients who had failed BCMA-directed CAR T cell therapy.

• The first phase 2 study of an allogeneic CAR T cell therapy is now open in the US; the CD19-directed cell product will be used to treat relapsed/refractory diffuse large B cell lymphoma.

• Allogeneic haploidentical CD45RA-depleted CAR T cells showed early efficacy in childhood B-ALL without significant induction of GvHD; however, persistence appears compromised compared with autologous CAR T cells.

• Real world data suggest that CAR T products are not equal, with axicabtagene ciloleucel showing superior outcomes to tisagenlecleucel in DLBCL, at the expensive of some additional toxicity.

• The first phase 2 clinical trial of an off the shelf allogeneic CAR T cell therapy is opening for patients with aggressive B cell lymphoma.

• Preclinical studies have explored combination bispecific antibody therapy for aggressive B cell lymphoma, combining CD20xCD3 and CD22xCD28 antibodies to provide two T cell signals.

• Loss of CD58, a ligand of CD2, resulted in resistance to CAR T cell therapy in preclinical studies; loss of function mutations are present in 6% of DLBCL (GENIE v8).

• In a retrospective study, 63% of DLBCL patients failed CAR T cell therapy (half primary resistance, half response then progression); 74% of CAR T failures received subsequent therapy with ORR 39% (CR 20%) but median EFS of only 1.9 months.

   

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.

• The FDA are launching a pilot project to explore a move away from the restrictive companion diagnostic model for biomarker associated drugs, towards allowing any suitably qualified assay to be used for biomarker detection.

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.

• The FDA have granted accelerated approval for the combination of a NECTIN4 ADC (enfortumab vedotin) and PD1 inhibitor (pembrolizumab) for advanced, platinum eligible disease, based on trial data showing ORR 68%, median DoR 22 months+.

   

ENDOMETRIAL

• The addition of PD1 inhibition to chemotherapy significantly improved PFS in microsatellite stable and unstable disease:
  • https://www.nejm.org/doi/full/10.1056/NEJMoa2216334
  • https://www.nejm.org/doi/full/10.1056/NEJMoa2302312

GENOMICS

• In a retrospective study, cancer patients with clonal haemopoiesis showed evidence of tumour microenvironment inflammation, particularly neutrophil activation.

OVARIAN

• Genomic studies identified enrichment of DNA repair pathway disruption and markers of anti-tumour immunity in longterm survivors of HGSOC; also of note, CCNE1 amplification was not always associated with poor outcome.

   

• In a randomised study, neither BRCA1/2 mutation nor homologous recombination deficiency were predictive of response to PDL1 inhibition (atezolizumab).

RENAL

• Combined inhibition of MET (savolitinib) and PDL1 (durvalumab) delivered ORR 29% in metastatic papillary cancer, increasing to 53% in MET-driven cancers (7% of renal papillary tumours), highlighting the importance of biomarker selection.