Cooper Andrews

Background: An estimated 1.4 million new cases of prostate cancer were diagnosed in 2020.¹ The first-line drug therapy for prostate cancer is Androgen Deprivation Therapy (ADT). However, Castration Resistant Prostate Cancer (CRPC) occurs in 10-20% of cases when the androgen receptor is mutated in a way that limits or negates the efficacy of ADT.^2,3 Patients with castration resistant prostate cancer show decreased overall survival and metastasis within 25-30 months.¹ Designed to bind CD3 on T cells and the Prostate Specific Membrane Antigen (PSMA) on prostate cancer cells, the PSMAxCD3 Bispecific Antibody (bsAb) can trigger T Cell mediated tumor lysis and is promising as a therapeutic option for CRPC.⁴ However, PSMAxCD3 bsAb therapy can cause the overexpression of IL-2, IL-6, IFNγ, and TNFα, i.e., Cytokine Release Syndrome (CRS). PSMAxCD3 bsAb also has demonstrated reduced efficacy against large solid tumors.^5,6,7 These obstacles need be overcome to improve the efficacy of the PSMAxCD3 bsAb in the management of CRPC.

Objective: In this narrative review, we summarized the recent mechanistic research seeking to improve the safety and efficacy of the PSMAxCD3 bsAb.

Search Methods: An online search in the PubMed database was conducted from 2017-2023 using the following keywords: “castration resistant prostate cancer”, “prostate specific membrane antigen”, “androgen deprivation therapy”, “PSMAxCD3 bispecific antibody”.

Results: One method of reducing CRS implemented a lower affinity CD3 arm in bsAb TNB-585 to lyse prostate tumors with lower levels of cytokine release.⁵ In both in vivo and ex vivo models, TNB-585 at doses with sufficient tumor killing activity demonstrated decreased cytokine inducing activity compared to the high affinity control.⁵ Another study found that Tocilizumab, an IL-6 receptor antibody, did not interfere with bsAb-mediated T cell activation or tumor cell lysis while attenuating symptoms of CRS.⁶ An in vitro study examining concurrent CD18 blockade with PSMAxCD3 bsAb found a reduction in off-target cytokine release without reduction in overall efficacy of therapy.⁸ Addressing efficacy against solid tumors, costimulation of receptor 4-1BB improved the efficacy of PSMAxCD3 bsAb in the lysis of large solid prostate tumors.⁹ In mice with large tumors (~200mm³), a combination of PSMAxCD3 bsAb and anti-4-1BB led to complete tumor clearance in 50% of mice after 60 days, while PSMAxCD3 alone was not sufficient to control tumors.⁹

Conclusion: Studies have found that a lower affinity CD3 arm and CD18 blockade can reduce the risk of CRS caused by PSMAxCD3 bsAb. IL-6 receptor antibody Tocilizumab was proven to attenuate CRS symptoms without diminishing anti-tumor efficacy of PSMAxCD3 bsAb. Costimulation of 4-1BB improved PSMAxCD3 bsAb efficacy against large solid tumors. Future consideration for an approach combining these strategies could potentially improve the clinical relevance of PSMAxCD3 bsAb in the management of CRPC.

Works Cited:

1. Turco F, Gillessen S, Cathomas R, Buttigliero C, Vogl UM. Treatment Landscape for Patients with Castration-Resistant Prostate Cancer: Patient Selection and Unmet Clinical Needs. Res Rep Urol. 2022;14:339-350. Published 2022 Sep 29. doi:10.2147/RRU.S360444
2. Vellky JE, Ricke WA. Development and prevalence of castration-resistant prostate cancer subtypes. Neoplasia. 2020;22(11):566-575. doi:10.1016/j.neo.2020.09.002
3. Kotamarti S, Armstrong AJ, Polascik TJ, Moul JW. Molecular Mechanisms of Castrate-Resistant Prostate Cancer. Urol Clin North Am. 2022;49(4):615-626. doi:10.1016/j.ucl.2022.07.005
4. Deegen P, Thomas O, Nolan-Stevaux O, et al. The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer. Clin Cancer Res. 2021;27(10):2928-2937. doi:10.1158/1078-0432.CCR-20-3725
5. Dang K, Castello G, Clarke SC, et al. Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release. J Immunother Cancer. 2021;9(6):e002488. doi:10.1136/jitc-2021-002488
6. Kauer J, Hörner S, Osburg L, et al. Tocilizumab, but not dexamethasone, prevents CRS without affecting antitumor activity of bispecific antibodies. J Immunother Cancer. 2020;8(1):e000621. doi:10.1136/jitc-2020-000621
7. Middelburg J, Kemper K, Engelberts P, Labrijn AF, Schuurman J, van Hall T. Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors. Cancers. 2021; 13(2):287. https://doi.org/10.3390/cancers13020287
8. Kauer J, Vogt F, Hagelstein I, et al. CD18 Antibody Application Blocks Unwanted Off-Target T Cell Activation Caused by Bispecific Antibodies. Cancers (Basel). 2021;13(18):4596. Published 2021 Sep 13. doi:10.3390/cancers13184596
9. Chiu D, Tavaré R, Haber L, et al. A PSMA-Targeting CD3 Bispecific Antibody Induces Antitumor Responses that Are Enhanced by 4-1BB Costimulation. Cancer Immunol Res. 2020;8(5):596-608. doi:10.1158/2326-6066.CIR-19-0518