Uncoupling toxicity from therapeutic efficacy: the new challenge of immunotherapies

3 min read
April 13, 2021

The emergence of immuno-oncology and, more specifically, checkpoint inhibitors have represented a ray of hope in the fight against cancer, offering the prospect of remission to patients suffering from diseases whose outcomes were previously invariably terminal. Among the most promising drugs is a monoclonal antibody targeting CTLA-4—ipilimumab—which has been the first checkpoint inhibitor to be tested and approved for the treatment of late-stage metastatic melanoma.1 It has been since shown that combination therapy targeting checkpoint inhibitors CTLA-4 and PD-1, such as ipilimumab and nivolumab, is even more effective than monotherapy that targets CTLA-4 alone. Indeed, the combined use of both these antibodies can greatly improve the outcome of patients affected by many types of cancers, including metastatic melanoma, renal cell carcinoma, colorectal cancer, and small cell lung cancer, compared to ipilimumab alone.2–4 Similar clinical benefits have been observed with a different CTLA-4/PD-1 combination therapy—tremelimumab and durvalumab—confirming that the combined use of checkpoint inhibitors represents a promising and efficient treatment for a broad range of tumors.5

Despite their clear potential, it is now broadly acknowledged that checkpoint inhibitors display a major limitation: the onset of immune-related adverse effects (irAEs). In layman’s terms, targeting the immune system to fight cancer cells can induce collateral damage in healthy organs, which poses a real dilemma. Therapies targeting CTLA-4, the “king” of immune checkpoint, perfectly illustrate this conundrum. CTLA-4 is known to prevent T-cell proliferation at the initial stages of naive T-cell activation.6 Under physiological conditions, it hampers autoimmunity and limits immune activation, thereby minimizing the potential collateral damages to healthy cells and tissues. Inhibition of CTLA-4 is thus associated with a wide range of side effects resembling autoimmune reactions.7 Several meta-analyses have shown that combination therapies can even increase the incidence and severity of irAEs, compared to monotherapies.8–11 As a consequence, these detrimental side effects are the number one reason why patients abandon clinical trials using anti-CTLA-4 ipilimumab mono- or combotherapies.8,9

To solve this cruel problem, a current major effort in immuno-oncology consists in developing new antibodies with reduced toxic effects. One way to achieve such a goal is to improve the tumor-targeted immunoreactivity of these compounds, thereby lowering the systemic T-cell activation at the origin of irAEs. For this purpose, bispecific antibodies (BsAbs) represent perfect candidates, as their dual specificity directs them toward the tumor site, thereby minimizing the risk of irAEs. Among those novel BsAbs are MEDI5752 and ATOR-1015, recently developed by AstraZeneca and Alligator Bioscience, respectively.12,13 The efficacy of these compounds was tested in immune checkpoint humanized preclinical models developed by genOway.


See also:

Uncoupling Toxicity from Therapeutic Efficacy: A Case Study on MEDI5752

Uncoupling Toxicity from Therapeutic Efficacy: A Case Study on ATOR-1015




  1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med. 2010;363(8):711-723. doi:10.1056/NEJMoa1003466
  2. Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res. 2019;38(1):255. doi:10.1186/s13046-019-1259-z
  3. Antonia SJ, LĂłpez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. The Lancet Oncology. 2016;17(7):883-895. doi:10.1016/S1470-2045(16)30098-5
  4. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020;11(1):3801. doi:10.1038/s41467-020-17670-y
  5. Wang B-C, Li P-C, Fan J-Q, Lin G-H, Liu Q. Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Medicine. 2020;99(28):e21273. doi:10.1097/MD.0000000000021273
  6. Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med. 1996;183(6):2533-2540. doi:10.1084/jem.183.6.2533
  7. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Front Oncol. 2018;8:86. doi:10.3389/fonc.2018.00086
  8. Omar NE, El-Fass KA, Abushouk AI, et al. Diagnosis and Management of Hematological Adverse Events Induced by Immune Checkpoint Inhibitors: A Systematic Review. Front Immunol. 2020;11:1354. doi:10.3389/fimmu.2020.01354
  9. Du X, Liu M, Su J, et al. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res. 2018;28(4):433-447. doi:10.1038/s41422-018-0012-z
  10. Da L, Teng Y, Wang N, et al. Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials. Front Pharmacol. 2019;10:1671. doi:10.3389/fphar.2019.01671
  11. Almutairi AR, McBride A, Slack M, Erstad BL, Abraham I. Potential Immune-Related Adverse Events Associated With Monotherapy and Combination Therapy of Ipilimumab, Nivolumab, and Pembrolizumab for Advanced Melanoma: A Systematic Review and Meta-Analysis. Front Oncol. 2020;10:91. doi:10.3389/fonc.2020.00091
  12. Dovedi SJ, Elder MJ, Yang C, et al. Design and efficacy of a monovalent bispecific PD-1/CTLA-4 antibody that enhances CTLA-4 blockade on PD-1+ activated T cells. Cancer Discov. Published online January 8, 2021. doi:10.1158/2159-8290.CD-20-1445
  13. Kvarnhammar AM, Veitonmäki N, Hägerbrand K, et al. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation. J Immunother Cancer. 2019;7(1):103. doi:10.1186/s40425-019-0570-8

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