@bgicli/bgicli 2.1.1 → 2.2.1

package/data/skills/tooluniverse-immunotherapy-response-prediction/SKILL.md

@@ -0,0 +1,865 @@
+---
+name: tooluniverse-immunotherapy-response-prediction
+description: Predict patient response to immune checkpoint inhibitors (ICIs) using multi-biomarker integration. Given a cancer type, somatic mutations, and optional biomarkers (TMB, PD-L1, MSI status), performs systematic analysis across 11 phases covering TMB classification, neoantigen burden estimation, MSI/MMR assessment, PD-L1 evaluation, immune microenvironment profiling, mutation-based resistance/sensitivity prediction, clinical evidence retrieval, and multi-biomarker score integration. Generates a quantitative ICI Response Score (0-100), response likelihood tier, specific ICI drug recommendations with evidence, resistance risk factors, and a monitoring plan. Use when oncologists ask about immunotherapy eligibility, checkpoint inhibitor selection, or biomarker-guided ICI treatment decisions.
+---
+
+# Immunotherapy Response Prediction
+
+Predict patient response to immune checkpoint inhibitors (ICIs) using multi-biomarker integration. Transforms a patient tumor profile (cancer type + mutations + biomarkers) into a quantitative ICI Response Score with drug-specific recommendations, resistance risk assessment, and monitoring plan.
+
+**KEY PRINCIPLES**:
+1. **Report-first approach** - Create report file FIRST, then populate progressively
+2. **Evidence-graded** - Every finding has an evidence tier (T1-T4)
+3. **Quantitative output** - ICI Response Score (0-100) with transparent component breakdown
+4. **Cancer-specific** - All thresholds and predictions are cancer-type adjusted
+5. **Multi-biomarker** - Integrate TMB + MSI + PD-L1 + neoantigen + mutations
+6. **Resistance-aware** - Always check for known resistance mutations (STK11, PTEN, JAK1/2, B2M)
+7. **Drug-specific** - Recommend specific ICI agents with evidence
+8. **Source-referenced** - Every statement cites the tool/database source
+9. **English-first queries** - Always use English terms in tool calls
+
+---
+
+## When to Use
+
+Apply when user asks:
+- "Will this patient respond to immunotherapy?"
+- "Should I give pembrolizumab to this melanoma patient?"
+- "Patient has NSCLC with TMB 25, PD-L1 80% - predict ICI response"
+- "MSI-high colorectal cancer - which checkpoint inhibitor?"
+- "Patient has BRAF V600E melanoma, TMB 15 - immunotherapy or targeted?"
+- "Low TMB NSCLC with STK11 mutation - should I try immunotherapy?"
+- "Compare pembrolizumab vs nivolumab for this patient profile"
+- "What biomarkers predict checkpoint inhibitor response?"
+
+---
+
+## Input Parsing
+
+**Required**: Cancer type + at least one of: mutation list OR TMB value
+**Optional**: PD-L1 expression, MSI status, immune infiltration data, HLA type, prior treatments, intended ICI
+
+### Accepted Input Formats
+
+| Format | Example | How to Parse |
+|--------|---------|-------------|
+| Cancer + mutations | "Melanoma, BRAF V600E, TP53 R273H" | cancer=melanoma, mutations=[BRAF V600E, TP53 R273H] |
+| Cancer + TMB | "NSCLC, TMB 25 mut/Mb" | cancer=NSCLC, tmb=25 |
+| Cancer + full profile | "Melanoma, BRAF V600E, TMB 15, PD-L1 50%, MSS" | cancer=melanoma, mutations=[BRAF V600E], tmb=15, pdl1=50, msi=MSS |
+| Cancer + MSI status | "Colorectal cancer, MSI-high" | cancer=CRC, msi=MSI-H |
+| Resistance query | "NSCLC, TMB 2, STK11 loss, PD-L1 <1%" | cancer=NSCLC, tmb=2, mutations=[STK11 loss], pdl1=0 |
+| ICI selection | "Which ICI for NSCLC PD-L1 90%?" | cancer=NSCLC, pdl1=90, query_type=drug_selection |
+
+### Cancer Type Normalization
+
+Common aliases to resolve:
+- NSCLC -> non-small cell lung carcinoma
+- SCLC -> small cell lung carcinoma
+- CRC -> colorectal cancer
+- RCC -> renal cell carcinoma
+- HNSCC -> head and neck squamous cell carcinoma
+- UC / bladder -> urothelial carcinoma
+- HCC -> hepatocellular carcinoma
+- TNBC -> triple-negative breast cancer
+- GEJ -> gastroesophageal junction cancer
+
+### Gene Symbol Normalization
+
+- PD-L1 -> CD274
+- PD-1 -> PDCD1
+- CTLA-4 -> CTLA4
+- HER2 -> ERBB2
+- MSH2/MLH1/MSH6/PMS2 -> MMR genes
+
+---
+
+## Phase 0: Tool Parameter Reference (CRITICAL)
+
+**BEFORE calling ANY tool**, verify parameters using this reference table.
+
+### Verified Tool Parameters
+
+| Tool | Parameters | Notes |
+|------|-----------|-------|
+| `OpenTargets_get_disease_id_description_by_name` | `diseaseName` | Returns `{data: {search: {hits: [{id, name, description}]}}}` |
+| `OpenTargets_get_drug_id_description_by_name` | `drugName` | Returns `{data: {search: {hits: [{id, name, description}]}}}` |
+| `OpenTargets_get_associated_drugs_by_disease_efoId` | `efoId`, `size` | Returns `{data: {disease: {knownDrugs: {count, rows}}}}` |
+| `OpenTargets_get_drug_mechanisms_of_action_by_chemblId` | `chemblId` | Returns `{data: {drug: {mechanismsOfAction: {rows}}}}` |
+| `OpenTargets_get_approved_indications_by_drug_chemblId` | `chemblId` | Approved indications list |
+| `OpenTargets_get_drug_description_by_chemblId` | `chemblId` | Drug description text |
+| `OpenTargets_get_associated_targets_by_drug_chemblId` | `chemblId` | Drug targets |
+| `MyGene_query_genes` | `query` (NOT `q`) | Returns `{hits: [{_id, symbol, name, ensembl: {gene}}]}` |
+| `ensembl_lookup_gene` | `gene_id`, `species='homo_sapiens'` | REQUIRES species. Returns `{data: {id, display_name}}` |
+| `EnsemblVEP_annotate_rsid` | `variant_id` (NOT `rsid`) | VEP annotation with SIFT/PolyPhen |
+| `civic_search_evidence_items` | `therapy_name`, `disease_name` | Returns `{data: {evidenceItems: {nodes}}}` - may not filter accurately |
+| `civic_search_variants` | `name`, `gene_name` | Returns `{data: {variants: {nodes}}}` - returns many unrelated variants |
+| `civic_get_variants_by_gene` | `gene_id` (CIViC numeric ID) | Requires CIViC gene ID, NOT Entrez |
+| `civic_search_assertions` | `therapy_name`, `disease_name` | Returns `{data: {assertions: {nodes}}}` |
+| `civic_search_therapies` | `name` | Search therapies by name |
+| `cBioPortal_get_mutations` | `study_id`, `gene_list` (string) | `gene_list` is a STRING not array |
+| `cBioPortal_get_cancer_studies` | (no params needed) | May fail with keyword param |
+| `drugbank_get_drug_basic_info_by_drug_name_or_id` | `query`, `case_sensitive`, `exact_match`, `limit` | ALL 4 REQUIRED |
+| `drugbank_get_targets_by_drug_name_or_drugbank_id` | `query`, `case_sensitive`, `exact_match`, `limit` | ALL 4 REQUIRED |
+| `drugbank_get_pharmacology_by_drug_name_or_drugbank_id` | `query`, `case_sensitive`, `exact_match`, `limit` | ALL 4 REQUIRED |
+| `drugbank_get_indications_by_drug_name_or_drugbank_id` | `query`, `case_sensitive`, `exact_match`, `limit` | ALL 4 REQUIRED |
+| `FDA_get_indications_by_drug_name` | `drug_name`, `limit` | Returns `{meta, results}` |
+| `FDA_get_clinical_studies_info_by_drug_name` | `drug_name`, `limit` | Returns `{meta, results}` |
+| `FDA_get_adverse_reactions_by_drug_name` | `drug_name`, `limit` | Returns `{meta, results}` |
+| `FDA_get_mechanism_of_action_by_drug_name` | `drug_name`, `limit` | Returns `{meta, results}` |
+| `FDA_get_boxed_warning_info_by_drug_name` | `drug_name`, `limit` | May return NOT_FOUND |
+| `FDA_get_warnings_by_drug_name` | `drug_name`, `limit` | Returns `{meta, results}` |
+| `fda_pharmacogenomic_biomarkers` | `drug_name`, `biomarker`, `limit` | Returns `{count, shown, results: [{Drug, Biomarker, TherapeuticArea, LabelingSection}]}` |
+| `clinical_trials_search` | `action='search_studies'`, `condition`, `intervention`, `limit` | Returns `{total_count, studies}` |
+| `clinical_trials_get_details` | `action='get_study_details'`, `nct_id` | Full study object |
+| `search_clinical_trials` | `query_term` (REQUIRED), `condition`, `intervention`, `pageSize` | Returns `{studies, total_count}` |
+| `PubMed_search_articles` | `query`, `max_results` | Returns plain list of dicts |
+| `UniProt_get_function_by_accession` | `accession` | Returns list of strings |
+| `UniProt_get_disease_variants_by_accession` | `accession` | Disease-associated variants |
+| `HPA_get_rna_expression_by_source` | `gene_name`, `source_type`, `source_name` | ALL 3 REQUIRED |
+| `HPA_get_cancer_prognostics_by_gene` | `gene_name` | Cancer prognostic data |
+| `iedb_search_epitopes` | `organism_name`, `source_antigen_name` | Returns `{status, data, count}` |
+| `iedb_search_mhc` | various | MHC binding data |
+| `enrichr_gene_enrichment_analysis` | `gene_list` (array), `libs` (array, REQUIRED) | Key libs: `KEGG_2021_Human`, `Reactome_2022` |
+| `PharmGKB_get_clinical_annotations` | `query` | Clinical annotations |
+| `gnomad_get_gene_constraints` | `gene_symbol` | Gene constraint metrics |
+
+---
+
+## Workflow Overview
+
+```
+Input: Cancer type + Mutations/TMB + Optional biomarkers (PD-L1, MSI, etc.)
+
+Phase 1: Input Standardization & Cancer Context
+  - Resolve cancer type to EFO ID
+  - Parse mutation list
+  - Resolve genes to Ensembl/Entrez IDs
+  - Get cancer-specific ICI baseline
+
+Phase 2: TMB Analysis
+  - TMB classification (low/intermediate/high)
+  - Cancer-specific TMB thresholds
+  - FDA TMB-H biomarker status
+
+Phase 3: Neoantigen Analysis
+  - Estimate neoantigen burden from mutations
+  - Mutation type classification (missense/frameshift/nonsense)
+  - Neoantigen quality indicators
+
+Phase 4: MSI/MMR Status Assessment
+  - MSI status integration
+  - MMR gene mutation check
+  - FDA MSI-H approval status
+
+Phase 5: PD-L1 Expression Analysis
+  - PD-L1 level classification
+  - Cancer-specific PD-L1 thresholds
+  - FDA-approved PD-L1 cutoffs
+
+Phase 6: Immune Microenvironment Profiling
+  - Immune checkpoint gene expression
+  - Tumor immune classification (hot/cold)
+  - Immune escape signatures
+
+Phase 7: Mutation-Based Predictors
+  - Driver mutation analysis
+  - Resistance mutations (STK11, PTEN, JAK1/2, B2M)
+  - Sensitivity mutations (POLE)
+  - DNA damage repair pathway
+
+Phase 8: Clinical Evidence & ICI Options
+  - FDA-approved ICIs for this cancer
+  - Clinical trial response rates
+  - Drug mechanism comparison
+  - Combination therapy evidence
+
+Phase 9: Resistance Risk Assessment
+  - Known resistance factors
+  - Tumor immune evasion mechanisms
+  - Prior treatment context
+
+Phase 10: Multi-Biomarker Score Integration
+  - Calculate ICI Response Score (0-100)
+  - Component breakdown
+  - Confidence level
+
+Phase 11: Clinical Recommendations
+  - ICI drug recommendation
+  - Monitoring plan
+  - Alternative strategies
+```
+
+---
+
+## Phase 1: Input Standardization & Cancer Context
+
+### Step 1.1: Resolve Cancer Type
+
+```python
+# Get cancer EFO ID
+result = tu.tools.OpenTargets_get_disease_id_description_by_name(diseaseName='melanoma')
+# -> {data: {search: {hits: [{id: 'EFO_0000756', name: 'melanoma', description: '...'}]}}}
+```
+
+**Cancer-specific ICI context** (hardcoded knowledge base):
+
+| Cancer Type | EFO ID | Baseline ICI ORR | Key Biomarkers | FDA-Approved ICIs |
+|-------------|--------|-------------------|----------------|-------------------|
+| Melanoma | EFO_0000756 | 30-45% | TMB, PD-L1 | pembro, nivo, ipi, nivo+ipi, nivo+rela |
+| NSCLC | EFO_0003060 | 15-50% (PD-L1 dependent) | PD-L1, TMB, STK11 | pembro, nivo, atezo, durva, cemiplimab |
+| Bladder/UC | EFO_0000292 | 15-25% | PD-L1, TMB | pembro, nivo, atezo, avelumab, durva |
+| RCC | EFO_0000681 | 25-40% | PD-L1 | nivo, pembro, nivo+ipi, nivo+cabo, pembro+axitinib |
+| HNSCC | EFO_0000181 | 15-20% | PD-L1 CPS | pembro, nivo |
+| MSI-H (any) | N/A | 30-50% | MSI, dMMR | pembro (tissue-agnostic) |
+| TMB-H (any) | N/A | 20-30% | TMB >=10 | pembro (tissue-agnostic) |
+| CRC (MSI-H) | EFO_0000365 | 30-50% | MSI, dMMR | pembro, nivo, nivo+ipi |
+| CRC (MSS) | EFO_0000365 | <5% | Generally poor | Generally not recommended |
+| HCC | EFO_0000182 | 15-20% | PD-L1 | atezo+bev, durva+treme, nivo+ipi |
+| TNBC | EFO_0005537 | 10-20% | PD-L1 CPS | pembro+chemo |
+| Gastric/GEJ | EFO_0000178 | 10-20% | PD-L1 CPS, MSI | pembro, nivo |
+
+### Step 1.2: Parse Mutations
+
+Parse each mutation into structured format:
+```
+"BRAF V600E" -> {gene: "BRAF", variant: "V600E", type: "missense"}
+"TP53 R273H" -> {gene: "TP53", variant: "R273H", type: "missense"}
+"STK11 loss" -> {gene: "STK11", variant: "loss of function", type: "loss"}
+```
+
+### Step 1.3: Resolve Gene IDs
+
+```python
+# For each gene in mutation list
+result = tu.tools.MyGene_query_genes(query='BRAF')
+# -> hits[0]: {_id: '673', symbol: 'BRAF', ensembl: {gene: 'ENSG00000157764'}}
+```
+
+---
+
+## Phase 2: TMB Analysis
+
+### Step 2.1: TMB Classification
+
+If TMB value provided directly, classify:
+
+| TMB Range | Classification | ICI Score Component |
+|-----------|---------------|---------------------|
+| >= 20 mut/Mb | TMB-High | 30 points |
+| 10-19.9 mut/Mb | TMB-Intermediate | 20 points |
+| 5-9.9 mut/Mb | TMB-Low | 10 points |
+| < 5 mut/Mb | TMB-Very-Low | 5 points |
+
+If only mutations provided, estimate TMB:
+- Count total mutations provided
+- Note: User-provided lists are typically key mutations, not full exome
+- Flag as "estimated from provided mutations - clinical TMB testing recommended"
+
+### Step 2.2: TMB FDA Context
+
+```python
+# Check FDA TMB-H biomarker approval
+result = tu.tools.fda_pharmacogenomic_biomarkers(drug_name='pembrolizumab', limit=100)
+# Look for "Tumor Mutational Burden" in Biomarker field
+# -> Pembrolizumab approved for TMB-H (>=10 mut/Mb) tissue-agnostic
+```
+
+### Step 2.3: Cancer-Specific TMB Thresholds
+
+| Cancer Type | Typical TMB Range | High-TMB Threshold | Notes |
+|-------------|-------------------|-------------------|-------|
+| Melanoma | 5-50+ | >20 | High baseline TMB; UV-induced |
+| NSCLC | 2-30 | >10 | Smoking-related; FDA cutoff 10 |
+| Bladder | 5-25 | >10 | Moderate baseline |
+| CRC (MSI-H) | 20-100+ | >10 | Very high in MSI-H |
+| CRC (MSS) | 2-10 | >10 | Generally low |
+| RCC | 1-8 | >10 | Low TMB but ICI-responsive |
+| HNSCC | 2-15 | >10 | Moderate |
+
+**IMPORTANT**: RCC responds to ICIs despite low TMB. TMB is less predictive in some cancers.
+
+---
+
+## Phase 3: Neoantigen Analysis
+
+### Step 3.1: Neoantigen Burden Estimation
+
+From mutation list:
+- **Missense mutations** -> Each has ~20-50% chance of generating a neoantigen
+- **Frameshift mutations** -> High neoantigen-generating potential (novel peptides)
+- **Nonsense mutations** -> Moderate potential (truncated proteins)
+- **Splice site mutations** -> Moderate potential (aberrant peptides)
+
+Estimate: neoantigen_count ~= missense_count * 0.3 + frameshift_count * 1.5
+
+### Step 3.2: Neoantigen Quality Assessment
+
+```python
+# Check mutation impact using UniProt
+result = tu.tools.UniProt_get_function_by_accession(accession='P15056')  # BRAF UniProt
+# Assess if mutation is in functional domain
+```
+
+**Quality indicators**:
+- Mutations in protein kinase domains -> high immunogenicity potential
+- Mutations in surface-exposed regions -> better MHC presentation
+- POLE/POLD1 mutations -> ultra-high neoantigen load (ultramutated)
+
+### Step 3.3: IEDB Epitope Data (if relevant)
+
+```python
+# Check known epitopes for mutated proteins
+result = tu.tools.iedb_search_epitopes(organism_name='homo sapiens', source_antigen_name='BRAF')
+# Returns known epitopes, MHC restrictions
+```
+
+### Neoantigen Score Component
+
+| Estimated Neoantigen Load | Classification | Score |
+|---------------------------|---------------|-------|
+| >50 neoantigens | High | 15 points |
+| 20-50 neoantigens | Moderate | 10 points |
+| <20 neoantigens | Low | 5 points |
+
+---
+
+## Phase 4: MSI/MMR Status Assessment
+
+### Step 4.1: MSI Status Integration
+
+If MSI status provided directly:
+
+| MSI Status | Classification | Score Component |
+|-----------|----------------|----------------|
+| MSI-H / dMMR | MSI-High | 25 points |
+| MSS / pMMR | Microsatellite Stable | 5 points |
+| Unknown | Not tested | 10 points (neutral) |
+
+### Step 4.2: MMR Gene Mutation Check
+
+Check if any provided mutations are in MMR genes:
+- **MLH1** (ENSG00000076242) - mismatch repair
+- **MSH2** (ENSG00000095002) - mismatch repair
+- **MSH6** (ENSG00000116062) - mismatch repair
+- **PMS2** (ENSG00000122512) - mismatch repair
+- **EPCAM** (ENSG00000119888) - can silence MSH2
+
+If MMR gene mutations found but MSI status not provided -> flag as "possible MSI-H, recommend testing"
+
+### Step 4.3: FDA MSI-H Approvals
+
+```python
+# Check FDA approvals for MSI-H
+result = tu.tools.fda_pharmacogenomic_biomarkers(biomarker='Microsatellite Instability', limit=100)
+# Pembrolizumab: tissue-agnostic for MSI-H/dMMR
+# Nivolumab: CRC (MSI-H)
+# Dostarlimab: dMMR solid tumors
+```
+
+---
+
+## Phase 5: PD-L1 Expression Analysis
+
+### Step 5.1: PD-L1 Level Classification
+
+| PD-L1 Level | Classification | Score Component |
+|-------------|----------------|----------------|
+| >= 50% (TPS) | PD-L1 High | 20 points |
+| 1-49% (TPS) | PD-L1 Positive | 12 points |
+| < 1% (TPS) | PD-L1 Negative | 5 points |
+| Unknown | Not tested | 10 points (neutral) |
+
+### Step 5.2: Cancer-Specific PD-L1 Thresholds
+
+| Cancer | Scoring Method | Key Thresholds | ICI Monotherapy Recommended? |
+|--------|---------------|----------------|------------------------------|
+| NSCLC | TPS | >=50%: first-line mono; >=1%: after chemo | Yes at >=50%, combo at >=1% |
+| Melanoma | Not routinely required | N/A | Yes regardless of PD-L1 |
+| Bladder | CPS or IC | CPS>=10 preferred | Yes with PD-L1 positive |
+| HNSCC | CPS | CPS>=1: pembro; CPS>=20: mono preferred | CPS>=20 for monotherapy |
+| Gastric | CPS | CPS>=1 | Pembro+chemo |
+| TNBC | CPS | CPS>=10 | Pembro+chemo |
+
+### Step 5.3: PD-L1 Gene Expression (Baseline Reference)
+
+```python
+# PD-L1 (CD274) expression patterns
+result = tu.tools.HPA_get_cancer_prognostics_by_gene(gene_name='CD274')
+# Cancer-type specific prognostic data
+```
+
+---
+
+## Phase 6: Immune Microenvironment Profiling
+
+### Step 6.1: Key Immune Checkpoint Genes
+
+Query expression data for immune microenvironment markers:
+
+```python
+# Key immune genes to check
+immune_genes = ['CD274', 'PDCD1', 'CTLA4', 'LAG3', 'HAVCR2', 'TIGIT', 'CD8A', 'CD8B', 'GZMA', 'GZMB', 'PRF1', 'IFNG']
+
+# For each gene, get cancer-specific expression
+for gene in immune_genes:
+    result = tu.tools.HPA_get_cancer_prognostics_by_gene(gene_name=gene)
+```
+
+### Step 6.2: Tumor Immune Classification
+
+Based on available data, classify:
+
+| Classification | Characteristics | ICI Likelihood |
+|---------------|-----------------|----------------|
+| Hot (T cell inflamed) | High CD8+ T cells, IFN-g, PD-L1+ | High response |
+| Cold (immune desert) | Low immune infiltration | Low response |
+| Immune excluded | Immune cells at margin, not infiltrating | Moderate response |
+| Immune suppressed | High Tregs, MDSCs, immunosuppressive | Low-moderate |
+
+### Step 6.3: Immune Pathway Enrichment
+
+```python
+# If mutation list includes immune-related genes, do pathway analysis
+result = tu.tools.enrichr_gene_enrichment_analysis(
+    gene_list=['CD274', 'PDCD1', 'CTLA4', 'IFNG', 'CD8A'],
+    libs=['KEGG_2021_Human', 'Reactome_2022']
+)
+```
+
+---
+
+## Phase 7: Mutation-Based Predictors
+
+### Step 7.1: ICI-Resistance Mutations (CRITICAL)
+
+**Known resistance mutations** - apply PENALTIES:
+
+| Gene | Mutation | Cancer Context | Mechanism | Penalty |
+|------|----------|---------------|-----------|---------|
+| STK11/LKB1 | Loss/inactivation | NSCLC (esp. KRAS+) | Immune exclusion, cold TME | -10 points |
+| PTEN | Loss/deletion | Multiple | Reduced T cell infiltration | -5 points |
+| JAK1 | Loss of function | Multiple | IFN-g signaling loss | -10 points |
+| JAK2 | Loss of function | Multiple | IFN-g signaling loss | -10 points |
+| B2M | Loss/mutation | Multiple | MHC-I loss, immune escape | -15 points |
+| KEAP1 | Loss/mutation | NSCLC | Oxidative stress, cold TME | -5 points |
+| MDM2 | Amplification | Multiple | Hyperprogression risk | -5 points |
+| MDM4 | Amplification | Multiple | Hyperprogression risk | -5 points |
+| EGFR | Activating mutation | NSCLC | Low TMB, cold TME | -5 points |
+
+### Step 7.2: ICI-Sensitivity Mutations (BONUS)
+
+| Gene | Mutation | Cancer Context | Mechanism | Bonus |
+|------|----------|---------------|-----------|-------|
+| POLE | Exonuclease domain | Any | Ultramutation, high neoantigens | +10 points |
+| POLD1 | Proofreading domain | Any | Ultramutation | +5 points |
+| BRCA1/2 | Loss of function | Multiple | Genomic instability | +3 points |
+| ARID1A | Loss of function | Multiple | Chromatin remodeling, TME | +3 points |
+| PBRM1 | Loss of function | RCC | ICI response in RCC | +5 points (RCC only) |
+
+### Step 7.3: Driver Mutation Context
+
+```python
+# For each mutation, check CIViC evidence for ICI context
+# Use OpenTargets for drug associations
+result = tu.tools.OpenTargets_get_associated_drugs_by_disease_efoId(efoId='EFO_0000756', size=50)
+# Filter for ICI drugs (pembro, nivo, ipi, atezo, durva, avelumab, cemiplimab)
+```
+
+### Step 7.4: DNA Damage Repair (DDR) Pathway
+
+Check if mutations are in DDR genes (associated with ICI response):
+- **ATM, ATR, CHEK1, CHEK2** - DNA damage sensing
+- **BRCA1, BRCA2, PALB2** - homologous recombination
+- **RAD50, MRE11, NBN** - double-strand break repair
+- **POLE, POLD1** - polymerase proofreading
+
+DDR mutations -> likely higher TMB -> better ICI response
+
+---
+
+## Phase 8: Clinical Evidence & ICI Options
+
+### Step 8.1: FDA-Approved ICIs
+
+```python
+# Get FDA indications for key ICIs
+ici_drugs = ['pembrolizumab', 'nivolumab', 'atezolizumab', 'durvalumab', 'ipilimumab', 'avelumab', 'cemiplimab']
+
+for drug in ici_drugs:
+    result = tu.tools.FDA_get_indications_by_drug_name(drug_name=drug, limit=3)
+    # Extract cancer-specific indications
+```
+
+### Step 8.2: ICI Drug Profiles
+
+| Drug | Target | Type | Key Indications |
+|------|--------|------|-----------------|
+| Pembrolizumab (Keytruda) | PD-1 | IgG4 mAb | Melanoma, NSCLC, HNSCC, Bladder, MSI-H, TMB-H, many others |
+| Nivolumab (Opdivo) | PD-1 | IgG4 mAb | Melanoma, NSCLC, RCC, CRC (MSI-H), HCC, HNSCC |
+| Atezolizumab (Tecentriq) | PD-L1 | IgG1 mAb | NSCLC, Bladder, HCC, Melanoma |
+| Durvalumab (Imfinzi) | PD-L1 | IgG1 mAb | NSCLC (Stage III), Bladder, HCC, BTC |
+| Ipilimumab (Yervoy) | CTLA-4 | IgG1 mAb | Melanoma, RCC (combo), CRC (MSI-H combo) |
+| Avelumab (Bavencio) | PD-L1 | IgG1 mAb | Merkel cell, Bladder (maintenance) |
+| Cemiplimab (Libtayo) | PD-1 | IgG4 mAb | CSCC, NSCLC, Basal cell |
+| Dostarlimab (Jemperli) | PD-1 | IgG4 mAb | dMMR endometrial, dMMR solid tumors |
+| Tremelimumab (Imjudo) | CTLA-4 | IgG2 mAb | HCC (combo with durva) |
+
+### Step 8.3: Clinical Trial Evidence
+
+```python
+# Search for ICI trials in this cancer type
+result = tu.tools.clinical_trials_search(
+    action='search_studies',
+    condition='melanoma',
+    intervention='pembrolizumab',
+    limit=10
+)
+# Returns: {total_count, studies: [{nctId, title, status, conditions}]}
+```
+
+### Step 8.4: Literature Evidence
+
+```python
+# Search PubMed for biomarker-specific ICI response data
+result = tu.tools.PubMed_search_articles(
+    query='pembrolizumab melanoma TMB response biomarker',
+    max_results=10
+)
+# Returns list of {pmid, title, ...}
+```
+
+### Step 8.5: OpenTargets Drug-Target Evidence
+
+```python
+# Get drug mechanism details
+result = tu.tools.OpenTargets_get_drug_mechanisms_of_action_by_chemblId(chemblId='CHEMBL3137343')
+# -> pembrolizumab: PD-1 inhibitor, targets PDCD1 (ENSG00000188389)
+```
+
+### Key ICI ChEMBL IDs
+
+| Drug | ChEMBL ID |
+|------|-----------|
+| Pembrolizumab | CHEMBL3137343 |
+| Nivolumab | CHEMBL2108738 |
+| Atezolizumab | CHEMBL3707227 |
+| Durvalumab | CHEMBL3301587 |
+| Ipilimumab | CHEMBL1789844 |
+| Avelumab | CHEMBL3833373 |
+| Cemiplimab | CHEMBL4297723 |
+
+---
+
+## Phase 9: Resistance Risk Assessment
+
+### Step 9.1: Known Resistance Factors Check
+
+For each mutation in the patient profile, check against resistance database:
+
+```python
+# Check for resistance evidence in CIViC
+# CIViC evidence types: PREDICTIVE, PROGNOSTIC, DIAGNOSTIC, PREDISPOSING, ONCOGENIC
+result = tu.tools.civic_search_evidence_items(therapy_name='pembrolizumab')
+# Filter for resistance-associated evidence
+```
+
+### Step 9.2: Pathway-Level Resistance
+
+| Pathway | Resistance Mechanism | Genes |
+|---------|---------------------|-------|
+| IFN-g signaling | Loss of IFN-g response | JAK1, JAK2, STAT1, IRF1 |
+| Antigen presentation | MHC-I downregulation | B2M, TAP1, TAP2, HLA-A/B/C |
+| WNT/b-catenin | T cell exclusion | CTNNB1 activating mutations |
+| MAPK pathway | Immune suppression | MEK, ERK hyperactivation |
+| PI3K/AKT/mTOR | Immune suppression | PTEN loss, PIK3CA |
+
+### Step 9.3: Resistance Risk Score
+
+Summarize resistance risk as:
+- **Low risk**: No resistance mutations, favorable TME
+- **Moderate risk**: 1 resistance factor OR uncertain TME
+- **High risk**: Multiple resistance mutations OR known resistant phenotype
+
+---
+
+## Phase 10: Multi-Biomarker Score Integration
+
+### ICI Response Score Calculation (0-100)
+
+```
+TOTAL SCORE = TMB_score + MSI_score + PDL1_score + Neoantigen_score + Mutation_bonus + Resistance_penalty
+
+Where:
+  TMB_score:        5-30 points (based on TMB classification)
+  MSI_score:        5-25 points (based on MSI status)
+  PDL1_score:       5-20 points (based on PD-L1 level)
+  Neoantigen_score: 5-15 points (based on estimated neoantigens)
+  Mutation_bonus:   0-10 points (POLE, PBRM1, etc.)
+  Resistance_penalty: -20 to 0 points (STK11, PTEN, JAK1/2, B2M)
+
+Minimum score: 0 (floor)
+Maximum score: 100 (cap)
+```
+
+### Response Likelihood Tiers
+
+| Score Range | Tier | Expected ORR | Recommendation |
+|-------------|------|-------------|----------------|
+| 70-100 | HIGH | 50-80% | Strong ICI candidate; monotherapy or combo |
+| 40-69 | MODERATE | 20-50% | Consider ICI; combo preferred; monitor closely |
+| 0-39 | LOW | <20% | ICI alone unlikely effective; consider alternatives |
+
+### Confidence Level
+
+| Data Completeness | Confidence |
+|-------------------|-----------|
+| All biomarkers (TMB + MSI + PD-L1 + mutations) | HIGH |
+| 3 of 4 biomarkers | MODERATE-HIGH |
+| 2 of 4 biomarkers | MODERATE |
+| 1 biomarker only | LOW |
+| Cancer type only | VERY LOW |
+
+---
+
+## Phase 11: Clinical Recommendations
+
+### Step 11.1: ICI Drug Selection Algorithm
+
+```
+IF MSI-H:
+  -> Pembrolizumab (tissue-agnostic FDA approval)
+  -> Nivolumab (CRC-specific)
+  -> Consider nivo+ipi combination
+
+IF TMB-H (>=10) and not MSI-H:
+  -> Pembrolizumab (tissue-agnostic for TMB-H)
+
+IF Cancer = Melanoma:
+  IF PD-L1 >= 1%: pembrolizumab or nivolumab monotherapy
+  ELSE: nivolumab + ipilimumab combination
+  IF BRAF V600E: consider targeted therapy first if rapid response needed
+
+IF Cancer = NSCLC:
+  IF PD-L1 >= 50% and no STK11/EGFR: pembrolizumab monotherapy
+  IF PD-L1 1-49%: pembrolizumab + chemotherapy
+  IF PD-L1 < 1%: ICI + chemotherapy combination
+  IF STK11 loss: ICI less likely effective
+  IF EGFR/ALK positive: targeted therapy preferred over ICI
+
+IF Cancer = RCC:
+  -> Nivolumab + ipilimumab (IMDC intermediate/poor risk)
+  -> Pembrolizumab + axitinib (all risk)
+
+IF Cancer = Bladder:
+  -> Pembrolizumab or atezolizumab (2L)
+  -> Avelumab maintenance post-platinum
+```
+
+### Step 11.2: Monitoring Plan
+
+**During ICI treatment, monitor**:
+- Tumor response (CT/MRI every 8-12 weeks)
+- Circulating tumor DNA (ctDNA) for early response
+- Immune-related adverse events (irAEs)
+- Thyroid function (TSH every 6 weeks)
+- Liver function (every 2-4 weeks initially)
+- Cortisol if symptoms
+
+**Early response biomarkers**:
+- ctDNA decrease at 4-6 weeks
+- PET-CT metabolic response
+- Circulating immune cell phenotyping
+
+### Step 11.3: Alternative Strategies
+
+If ICI response predicted to be LOW:
+1. **Targeted therapy** (if actionable mutations: BRAF, EGFR, ALK, ROS1)
+2. **Chemotherapy** (standard of care)
+3. **ICI + chemotherapy combination** (may overcome low PD-L1)
+4. **ICI + anti-angiogenic** (may convert cold to hot tumor)
+5. **ICI + CTLA-4 combo** (nivolumab + ipilimumab)
+6. **Clinical trial enrollment** (novel combinations)
+
+---
+
+## Output Report Format
+
+Save report as `immunotherapy_response_prediction_{cancer_type}.md`
+
+### Report Structure
+
+```markdown
+# Immunotherapy Response Prediction Report
+
+## Executive Summary
+[2-3 sentence summary: cancer type, ICI Response Score, recommendation]
+
+## ICI Response Score: XX/100
+**Response Likelihood: [HIGH/MODERATE/LOW]**
+**Confidence: [HIGH/MODERATE/LOW]**
+**Expected ORR: XX-XX%**
+
+### Score Breakdown
+| Component | Value | Score | Max |
+|-----------|-------|-------|-----|
+| TMB | XX mut/Mb | XX | 30 |
+| MSI Status | MSI-H/MSS | XX | 25 |
+| PD-L1 | XX% | XX | 20 |
+| Neoantigen Load | XX est. | XX | 15 |
+| Sensitivity Bonus | +XX | XX | 10 |
+| Resistance Penalty | -XX | XX | -20 |
+| **TOTAL** | | **XX** | **100** |
+
+## Patient Profile
+- **Cancer Type**: [cancer]
+- **Mutations**: [list]
+- **TMB**: XX mut/Mb [classification]
+- **MSI Status**: [MSI-H/MSS/Unknown]
+- **PD-L1**: XX% [scoring method]
+
+## Biomarker Analysis
+
+### TMB Analysis
+[TMB classification, cancer-specific context, FDA TMB-H status]
+
+### MSI/MMR Status
+[MSI status, MMR gene mutations, FDA MSI-H approvals]
+
+### PD-L1 Expression
+[PD-L1 level, cancer-specific thresholds, scoring method]
+
+### Neoantigen Burden
+[Estimated neoantigen count, quality assessment, mutation types]
+
+## Mutation Analysis
+
+### Driver Mutations
+[Analysis of each mutation - oncogenic role, ICI implications]
+
+### Resistance Mutations
+[Any STK11, PTEN, JAK1/2, B2M, KEAP1 etc. with penalties]
+
+### Sensitivity Mutations
+[Any POLE, PBRM1, DDR genes with bonuses]
+
+## Immune Microenvironment
+[Hot/cold classification, immune gene expression data]
+
+## ICI Drug Recommendation
+
+### Primary Recommendation
+**[Drug name]** - [monotherapy/combination]
+- Evidence: [FDA approval, trial data]
+- Expected response: XX-XX%
+- Key trial: [trial name/NCT#]
+
+### Alternative Options
+1. [Alternative 1] - [rationale]
+2. [Alternative 2] - [rationale]
+
+### Combination Strategies
+[ICI+ICI, ICI+chemo, ICI+targeted recommendations]
+
+## Clinical Evidence
+[Key trials, response rates, PFS/OS data for this cancer + biomarker profile]
+
+## Resistance Risk
+- **Risk Level**: [LOW/MODERATE/HIGH]
+- **Key Factors**: [list resistance mutations/mechanisms]
+- **Mitigation**: [combination strategies]
+
+## Monitoring Plan
+- **Response assessment**: [schedule]
+- **Biomarkers to track**: [ctDNA, imaging, labs]
+- **irAE monitoring**: [schedule]
+- **Resistance monitoring**: [when to suspect progression]
+
+## Alternative Strategies (if ICI unlikely effective)
+[Targeted therapy, chemotherapy, clinical trials]
+
+## Evidence Grading
+| Finding | Evidence Tier | Source |
+|---------|-------------|--------|
+| [finding 1] | T1 (FDA/Guidelines) | [source] |
+| [finding 2] | T2 (Clinical trial) | [source] |
+
+## Data Completeness
+| Biomarker | Status | Impact |
+|-----------|--------|--------|
+| TMB | Provided/Estimated/Unknown | XX points |
+| MSI | Provided/Unknown | XX points |
+| PD-L1 | Provided/Unknown | XX points |
+| Neoantigen | Estimated | XX points |
+| Mutations | X provided | +/-XX points |
+
+## Missing Data Recommendations
+[What additional tests would improve prediction accuracy]
+
+---
+*Generated by ToolUniverse Immunotherapy Response Prediction Skill*
+*Sources: OpenTargets, CIViC, FDA, DrugBank, PubMed, IEDB, HPA, cBioPortal*
+```
+
+---
+
+## Evidence Tiers
+
+| Tier | Description | Source Examples |
+|------|-------------|----------------|
+| T1 | FDA-approved biomarker/indication | FDA labels, NCCN guidelines |
+| T2 | Phase 2-3 clinical trial evidence | Published trial data, PubMed |
+| T3 | Preclinical/computational evidence | Pathway analysis, in vitro data |
+| T4 | Expert opinion/case reports | Case series, reviews |
+
+---
+
+## Use Case Examples
+
+### Use Case 1: NSCLC with High TMB
+**Input**: "NSCLC, TMB 25, PD-L1 80%, no STK11 mutation"
+**Expected**: ICI Score 70-85, HIGH response, pembrolizumab monotherapy recommended
+
+### Use Case 2: Melanoma with BRAF
+**Input**: "Melanoma, BRAF V600E, TMB 15, PD-L1 50%"
+**Expected**: ICI Score 50-65, MODERATE response, discuss ICI vs BRAF-targeted
+
+### Use Case 3: MSI-H Colorectal
+**Input**: "Colorectal cancer, MSI-high, TMB 40"
+**Expected**: ICI Score 80-95, HIGH response, pembrolizumab first-line
+
+### Use Case 4: Low Biomarker NSCLC
+**Input**: "NSCLC, TMB 2, PD-L1 <1%, STK11 mutation"
+**Expected**: ICI Score 5-20, LOW response, chemotherapy preferred
+
+### Use Case 5: Bladder Cancer
+**Input**: "Bladder cancer, TMB 12, PD-L1 10%, no resistance mutations"
+**Expected**: ICI Score 45-55, MODERATE response, ICI+chemo or maintenance
+
+### Use Case 6: Checkpoint Inhibitor Selection
+**Input**: "Which ICI for NSCLC with PD-L1 90%?"
+**Expected**: Pembrolizumab monotherapy first-line, evidence from KEYNOTE-024
+
+---
+
+## Completeness Checklist
+
+Before finalizing the report, verify:
+
+- [ ] Cancer type resolved to EFO ID
+- [ ] All mutations parsed and genes resolved
+- [ ] TMB classified with cancer-specific context
+- [ ] MSI/MMR status assessed
+- [ ] PD-L1 integrated (or flagged as unknown)
+- [ ] Neoantigen burden estimated
+- [ ] Resistance mutations checked (STK11, PTEN, JAK1/2, B2M, KEAP1)
+- [ ] Sensitivity mutations checked (POLE, PBRM1, DDR)
+- [ ] FDA-approved ICIs identified for this cancer
+- [ ] Clinical trial evidence retrieved
+- [ ] ICI Response Score calculated with component breakdown
+- [ ] Drug recommendation provided with evidence
+- [ ] Monitoring plan included
+- [ ] Alternative strategies for low responders
+- [ ] Evidence grading applied to all findings
+- [ ] Data completeness documented
+- [ ] Missing data recommendations provided
+- [ ] Report saved to file