Combination immunotherapy seeks to integrate modalities—such as oncolytic viruses (OVs), chemotherapy, radiation, CAR-T cells, and BiTEs. 
 
𝗪𝗵𝘆 𝗖𝗼𝗺𝗯𝗶𝗻𝗲 𝗧𝗵𝗲𝗿𝗮𝗽𝗶𝗲𝘀? 
𝘚𝘺𝘯𝘦𝘳𝘨𝘺 𝘰𝘧 𝘮𝘦𝘤𝘩𝘢𝘯𝘪𝘴𝘮𝘴: OVs can lyse tumor cells and release neoantigens, sensitizing ´cold´ tumors to immune checkpoint blockade (ICB) or CAR-T therapy. 
Overcoming immune suppression: Radiation or chemotherapy may deplete immunosuppressive cells (Tregs), remodel the TME, and enhance T‑cell infiltration. 
𝘙𝘦𝘥𝘶𝘤𝘪𝘯𝘨 𝘳𝘦𝘴𝘪𝘴𝘵𝘢𝘯𝘤𝘦: Targeting multiple pathways reduces the chance that tumor clones will escape through a single mechanism. 
 
𝗢𝗩𝘀 + 𝗥𝗮𝗱𝗶𝗮𝘁𝗶𝗼𝗻 + ICB
Preclinical data – triple combination converts immune ´cold´ tumors into ´hot´ ones, driving CD8+ T cell–mediated responses and improved survival. [1] Clinical case reports in PD-1–refractory cancer – may rescue response in challenging settings. [1] 
 
CAR-T + Chemo or Radio/Chemo- conditioning 
Mathematical models support that combining CAR-T therapy with chemotherapy can maximize tumor eradication by reducing immunosuppressive tumor burden and enhancing CAR-T cell expansion. [2] In glioma, radioimmunotherapy with PD‑L1 or CTLA‑4 blockade shows promising synergy. [3] 
 
Bispecific/BiTEs as backbone + Other Therapies
BioNTech’s bispecific antibody BNT327 (PD-L1 × VEGF-A) is being developed in partnership with BMS. Simultaneously targets immune suppression (PD-L1) and angiogenesis (VEGF-A), positioning it as a potential backbone for multi-modal immuno-oncology. [4] 
 
Challenges in Clinical Interpretation
• Complex toxicity profiles: Combining agents increases the risk of immune-related adverse events. 
• Trial design complexity: Tracking the contribution of each modality is difficult. 
• Biomarkers: Reliable predictive biomarkers are still lacking for individual patients. 
• Regulatory hurdles: Safety and manufacturing of multi-agent regimens are more demanding. 
 
𝗤𝘂𝗲𝘀𝘁𝗶𝗼𝗻 𝗳𝗼𝗿 𝘁𝗵𝗲 𝗔𝘂𝗱𝗶𝗲𝗻𝗰𝗲 
Which combination is most promising for solid tumors: OV + ICB, or OV + CAR-T, and why? 
 
Stay tuned for 𝗗𝗮𝘆 𝟲𝟳: 𝗙𝗿𝗼𝗺 𝗕𝗲𝗻𝗰𝗵 𝘁𝗼 𝗕𝗲𝗱𝘀𝗶𝗱𝗲  𝗖𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝗧𝗿𝗶𝗮𝗹 𝗦𝘁𝗮𝗴𝗲𝘀 𝗶𝗻 𝗠𝗼𝗱𝗲𝗿𝗻 𝗖𝗮𝗻𝗰𝗲𝗿 𝗜𝗺𝗺𝘂𝗻𝗼𝘁𝗵𝗲𝗿𝗮𝗽𝘆 
 
𝗥𝗲𝗳𝗲𝗿𝗲𝗻𝗰𝗲𝘀 
1. https://lnkd.in/eXyFnehi 
2. DOI: 10.1063/5.0260252 
3. DOI:10.1109/TCBB.2022.3174454 
4. https://lnkd.in/eMDBNzZf 

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