Abstract CT086: Phase I study of intravesical Fc-optimized anti-CD40 agonist antibody 2141-V11 for non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) therapy
Juan C. OsorioMuneeb AlamJeffrey L. WongDavid A. KnorrLucas BlanchardJuan Carlos Angulo-LozanoKarissa WhitingVenkatraman SeshanTimothy F. DonahueK. EugeneAlvin C. GohRobert P. SmithGuido DalbagniChristian HernandezMelissa McCarterEugene J. PietzakJonathan E. RosenbergJeffrey V. RavetchBernard H. Bochner
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Abstract Introduction: The CD40-CD40L pathway is crucial for activating antigen-presenting cells and initiating tumor-specific T cell responses across various malignancies. However, prior agonistic anti-CD40 antibodies have encountered limited clinical success and significant toxicity. Our previous studies demonstrate that interactions between the antibody Fc domain and the inhibitory Fc-gamma receptor FcγRIIB are critical for efficient CD40 multimerization and enhanced antitumor activity. To optimize this interaction, we developed 2141-V11, a novel anti-CD40 antibody Fc-engineered to increase binding affinity for FcγRIIB, resulting in effective antitumor activity in both in vivo and in a recent first-in-human phase I trial (NCT04059588). Non-muscle invasive bladder cancer (NMIBC) is the most common presentation of bladder cancer, with a high risk of recurrence and progression despite optimal surgical interventions and standard therapies. Bacillus Calmette-Guerin (BCG) intravesical treatment has been the standard of care for NMIBC over the last five decades. However, 75% of patients ultimately become unresponsive to this therapy, leaving limited curative options aside from complete radical cystectomy. Using several preclinical bladder cancer models, including BCG-unresponsive disease, we found that intravesical administration of 2141-V11 induces durable anti-tumor immunity without systemic toxicity. Based on these findings, we initiated a Phase I study of intravesical 2141-V11 for the treatment of BCG-unresponsive NMIBC. Methods: This is an investigator-initiated Phase I, open-label, dose-escalation study to evaluate the safety and tolerability of intravesical 2141-V11 in patients with BCG-unresponsive NMIBC (N=25) who are ineligible for or decline radical cystectomy (NCT05126472). Following complete transurethral resection, intravesical 2141-V11 is administered once weekly for three doses, with re-treatment eligibility at week 13 and 25, based on disease status determined by on-treatment biopsies. The study follows an MCRM dose escalation design with five dose levels (0.7, 2.0, 7.0, 21.0 and 70.0 mg). Primary endpoints include safety and dose tolerability to determine maximal tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Secondary endpoints involve pharmacokinetic profiling and preliminary evaluation of clinical activity. Exploratory objectives include investigation of biological markers of drug activity in pre- and post-treatment tissue biopsies and urine biospecimens. As of the data cutoff on 12/20/23, 80% of the planned patients (n=20) have been enrolled, with no dose-limiting toxicities observed. Accrual completion is expected by the first quarter of 2024, with ongoing analysis of urine immune profiling, cytokine analysis, as well as single-cell spatial phenotyping in pre- and post-treatment samples. Citation Format: Juan C. Osorio, Muneeb Alam, Jeffrey Wong, David Knorr, Lucas Blanchard, Juan C. Angulo-Lozano, Karissa Whiting, Venkatraman E. Seshan, Timothy F. Donahue, Eugene K. Cha, Alvin C. Goh, Robert Smith, Guido Dalbagni, Christian Hernandez, Melissa McCarter, Eugene J. Pietzak, Jonathan E. Rosenberg, Jeffrey V. Ravetch, Bernard H. Bochner. Phase I study of intravesical Fc-optimized anti-CD40 agonist antibody 2141-V11 for non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT086.Cite
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Quantitation of agonist concentration-response curves yields information regarding the agonist potency and maximum effect. The potency is well known to be dependent on both drug and tissue factors (agonist efficacy and affinity, tissue receptor reserve and stimulus-response coupling efficiency). The agonist maximum effect is a function of the agonist efficacy and the tissue properties of receptor reserve and stimulus-response coupling efficiency. However, when the agonist has sufficient efficacy to maximally activate the tissue, the maximum effect of the agonist becomes a property only of the tissue: the tissue maximum response. A new protocol has been devised that allows the generation of extended concentration-response curves that overcome the tissue maximum response as a constraint on the maximum measured effect of an agonist. This protocol has been called the up/down protocol.
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순천향대학교 천안병원 산부인과 외래에 내원한 1995년 3월부터 1997년 2월까지의 자궁근종으로 진단된 환자 중 약물치료(GnRH agonist)의 경험이 있는 45명을 대상으로 GnRH agonist(Decapeptyl, Leuprolide, Nafarelin)의 자궁근종에 대한 효과와 부작용에 대해 관찰한 결과는 다음과 같다. 1. 6개월간의 호르몬 약물치료를 받았던 45명 중 3명을 제외한 42(93.3%)명의 환자에서 마지막 약물 투여 후의 자궁근종의 크기는 처음의 42.8 ± 4.4% 로 모두 부피감소 소견을 나타냈다(p ＜ 0.005). 45명 중 27(60%)명은 수술을 용이하게 할 수 있었고 출혈 등의 합병증을 줄일 수 있었으며 나머지 18명(40%) 중 15(33.3%)명은 약물치료만으로 만족한 효과를 얻 을 수 있었고 나머지 3명(6.7%)은 6개월 후에 GnRH agonist의 종류를 교체한 경우로 치료 효과는 저조한 경우로 판단하였다. 2. 6개월간의 약물 투여 기간 중 LH와 FSH의 유 효한 혈중치 저하소견은 보이지 않았으나(p ＞ 0.05) Estradiol의 혈중치는 치료 시작 전 148.7 ± 20.5 pg/ml에서 치료 시작 4주에 29.7 ± 19.5pg/ml, 치료 24주 후 17.9 ± 10.9 pg/ml로 급속히 감소하는 소견 을 나타냈다(p ＜ 0.005). 3. 자궁근종으로 인한 임상증상은 치료시작 4∼8 주부터 서서히 완화되었거나 없어졌다. 4. 마지막 약물치료 후 4주후부터 estradiol치는 25 ± 14.8pg/ml로 서서히 증가하는 소견을 나타냈고 소 퇴했던 자궁근종의 크기도 약물투여시 42.8 ± 4.4% 에서 치료종료 8주 후 49.6 ± 2.7%로 서서히 증가 하기 시작했다(p ＜ 0.05). 5. 부작용으로는 안면홍조(82.2%)가 가장 많았고 질건조감(37.8%), 피로감 및 의욕저하(46.7%), 두통이 나 불면증(33.37%) 등이 있었고 전신무력감, 체중변 화 또는 골조소증 증상 소견은 미약했으며, 부작용 때문에 치료를 중단한 예는 없었고 치료 종료 후 월 경이 다시 시작되면서 부작용은 모두 소실되었다. 6. 약물치료 후 개복술을 시행하여 전자궁적출술 이나 자궁근종절제술을 시도한 결과 약제를 쓰지않 고 수술을 한 경우에 비하여 훨씬 수술이 용이하였 고 출혈도 적었으며 수술 후 합병증도 적었다. 7. 본 연구에서 사용된 GnRH agonist로는 Deca peptyl, Leuprolide, Nafarelin이고 각각의 효용성이나 부작용에 대한 별다른 차이점은 없었다. 본 연구 결과를 토대로 GnRH agonist의 자궁근종 에 대한 치료효과는 매우 탁월하다고 사료된다. 그 러나 약물투여중에 나타날 수 있는 저에스트로젠 의 존성 부작용(GnRH agonist induced estrogen dependent side effects)을 줄이기 위한 노력(그예로: two step GnRH agonist treatment, or add back regimen)이 현재 많이 시도되고 있는 것으로 알려져 있는 것으로 안 다. 이에 새로운 약물치료 방법의 도입과 연구가 필 요하리라 사료되며 또한 치료중단 후의 자궁근종의 빠른 재성장에 대한 대처요법의 많은 연구보고가 있 어야 할 것으로 사료된다.
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Bladder cancer is the fourth most common cancer in men, with an estimated diagnosis of 60,490 new cases and 12,240 deaths in the United States in 2017 (1). Nearly 75% of bladder cancer patients are diagnosed with non-muscle invasive bladder cancer (NMIBC), which consists of stages Ta, T1, and carcinoma in situ (CIS). NMIBC is rarely lethal, but 50–70% of patients experience disease recurrence and 10–30% of patients' progress to life-threatening muscle-invasive bladder cancer (MIBC) (2).
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Functional interactions between several contractile agonists were examined in the guinea pig isolated trachea. Cumulative concentration-response effects of agonist A were obtained in the absence and presence of steady-state contractions induced by agonist B. The agonists examined included histamine, prostaglandin D2, platelet activating factor, leukotrienes E4 and D4 and carbamylcholine. We found that none of the agonists studied caused a leftward shift in the concentration-response curve of a second agonist, nor did any agonist decrease the concentration of a second agonist required to evoke a maximum response. In general the functional interactions fit the predictions based on the early models of functional additivity. However, the interactions deviated categorically from this model in that there was less than predicted additivity at concentrations of the interactants that alone induced greater than a 50% response. The degree to which this deviation occurred was agonist dependent. The results suggest that in the guinea pig trachea a contractile agonist does not uncover or increase a reserve in the receptor-subeffect-response chain of a second contractile agonist. The findings that the quantitative nature of the interactions were somewhat agonist dependent supports the hypothesis that more than one biochemical mechanism is involved in the receptor-mediated contraction of airway smooth muscle.
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The time‐honored approach of quantifying agonist selectivity through measurement of agonist affinity with binding and efficacy through potency ratios in model assays for prediction of effect in therapeutic systems can fall short of providing useful answers for functionally selective agonists. Agonists are now known to have pluridimensional efficacies that are associated with selected signalling pathways coupled to the receptor. This necessitates specifically tailored assay formats to measure pre‐determined efficacies of ligands to characterize agonist selectivity fully. If such assays can access signalling that directly emanates from the interaction of the agonist‐bound receptor and a cytosolic signalling protein, then the Black/Leff operational model can be used to specifically quantify ‘transduction ratios’ (τ/ K A ) that fully characterize selective activation of signalling pathways by a given agonist. As whole‐cell processing of pleiotropic signalling cascades imposes cell‐specific phenotypic agonist profiles, ultimately the assessment of agonist selectivity is most reliably done in the therapeutically relevant primary cell system. This article is a commentary on Baker, pp. 1048–1061 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00754.x
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