P2, N=3, Terminated, Gwynn Long, M.D. | N=10 --> 3 | Trial completion date: Dec 2024 --> Nov 2022 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Nov 2022; ADCT is reallocating all resources to the phase III program.

Clinical studies on novel agents, including brentuximab vedotin (BV) and PD-1 inhibitors, have successfully demonstrated their effectiveness in relapsed disease after ASCT. Additionally, studies examining combination strategies with the goal of reducing the risk of relapse and chemotherapy-related toxicity have showed encouraging results, mainly in untreated early unfavorable or advanced stage classical HL (cHL). Other non-approved immunotherapies such as camidanlumab tesirine, bispecific CD30/CD16A antibody, and CD30 chimeric antigen receptor (CAR) T-cell therapy are promising approaches that may reinforce the therapeutic arsenal available to patients.

Most cases of ALK+ ALCL highly express CD25 indicating that CD25 is a potential therapeutic target for ALCL patients. In this study, low CD25 expression identified a subset of ALK+ ALCL cases associated with older patient age, thrombocytopenia and shorter OS. These data suggest that assessing CD25 in ALK+ ALCL may be useful for guiding targeted therapy and in predicting prognosis of patients with ALK+ ALCL.

P1b, N=78, Terminated, ADC Therapeutics S.A. | Trial completion date: Nov 2023 --> Nov 2022 | Recruiting --> Terminated; Cami in combination with pembrolizumab in solid tumors showed signals of immunomodulatory activity. However, the signals were insufficiently compelling at the tested dose/schedule to justify continuation of the study.

The pivotal phase 2 trial showed significant antitumor activity of camidanlumab tesirine in heavily pretreated R/R cHL patients who failed brentuximab vedotin and programmed death-1 blockade: ORR was 70.1% and CRR was 33.3%, and the median duration of response was 13.7 months. Adverse events such as fatigue, maculopapular rash, and anemia were frequently observed following administration of camidanlumab tesirine. Moreover, camidanlumab tesirine may cause Guillain-Barré syndrome or polyradiculopathy.

The final model described the observed data well, estimates of PK parameters were obtained, and covariates with significant effects on Cami exposure were identified. Altogether, this final PPK model provides a robust basis for analysis of Cami exposure-response relationships and further supports identification of the optimal Cami dosing schedule for patients with relapsed/refractory lymphoma.

Higher median tumor cell CD25 H-score was seen in responders vs nonresponders in all and recent biopsies but the differences did not reach significance. These data warrant further investigations as phase 1 data showed significantly higher tumor CD25 expression in responders (Hamadani, et al. 2021).

PK exposure of Cami was dose-related with varying degrees of interpatient variability. Circulating Tregs were significantly decreased and Teff:Treg was significantly increased by Cami exposure, demonstrating the intended immunomodulatory effect of Cami in circulation and suggesting that a combination approach with Cami could address an immune-resistance mechanism. Future analyses will consider discrete PEM effect, correlates to tumor biopsy expression and response, and combined Cami+PEM effect in tumor biopsies.

In the past decade, novel therapies including, brentuximab vedotin, PD-1 inhibitors, and the incorporation of PET-imaging into management have changed the paradigm of relapsed/refractory disease care. There is promising early work into the utility of CD30.CAR-T cell therapy, AFM13, camidanlumab tesirine, novel PD-1 inhibitors, and JAK1/JAK2 inhibition in management. Herein, we will review current salvage therapies in Hodgkin lymphoma and future directions in relapsed/refractory disease management.

While these data support the rational to target CD25, ALL cells did not appear to be in-vitro sensitive to basiliximab, an antibody able to target the Il2RA, but in-vivo investigations are needed to better assess the effects of this therapeutic approach in ALL context...Targeting CD25 receptor with anti-CD25 antibodies or peptide mimetics could be an effective strategy for targeting leukemic cells. Additionally, high CD25 expression could be exploited for the development of CAR-T therapy

While these data support the rational to target CD25, ALL cells did not appear to be in-vitro sensitive to basiliximab, an antibody able to target the Il2RA, but in-vivo investigations are needed to better assess the effects of this therapeutic approach in ALL context...Targeting CD25 receptor with anti-CD25 antibodies or peptide mimetics could be an effective strategy for targeting leukemic cells. Additionally, high CD25 expression could be exploited for the development of CAR-T therapy

While these data support the rational to target CD25, ALL cells did not appear to be in-vitro sensitive to basiliximab, an antibody able to target the Il2RA, but in-vivo investigations are needed to better assess the effects of this therapeutic approach in ALL context...Targeting CD25 receptor with anti-CD25 antibodies or peptide mimetics could be an effective strategy for targeting leukemic cells. Additionally, high CD25 expression could be exploited for the development of CAR-T therapy

While these data support the rational to target CD25, ALL cells did not appear to be in-vitro sensitive to basiliximab, an antibody able to target the Il2RA, but in-vivo investigations are needed to better assess the effects of this therapeutic approach in ALL context...Targeting CD25 receptor with anti-CD25 antibodies or peptide mimetics could be an effective strategy for targeting leukemic cells. Additionally, high CD25 expression could be exploited for the development of CAR-T therapy

These results suggest that our novel CD38 siRNA co-expressing CD38-JAK-STAT CAR-T cells manufactured with dasatinib treatment may persist longer and induce potent antigen-specific response with minimal excessive unfavorable activation, which results in maximal efficacy. This approach can be applied to other CAR-T cells targeting the shared antigen expressed on T cells.

The field of immunotherapy in cHL is now moving toward combinations of PD-1 inhibitors with other immunological agents such as cytotoxic T- lymphocyte associated protein-4 (CTLA-4) inhibitors, newer PD-1 inhibitors such as sintilimab, tislelizumab, avelumab and camrelizumab, bispecific antibodies such as AFM-13, cellular therapies using CD30 chimeric antigen T-cells (CD30.CART) and anti-CD25 antibody-drug conjugates such as camidanlumab tesirine (cami-T). Here we review early phase studies evaluating these approaches in the treatment of cHL.

There are limited treatment options for relapsed/refractory classical Hodgkin lymphoma (cHL) patients who progress on brentuximab vedotin and programmed death-1 inhibitors. The toxicity profile was similar to that seen in the phase 1 study, with no new safety signals.. As the phase 2 study with Cami is continuing to accrue patients and we await the final results, the preliminary results with Cami are encouraging and provide an additional therapeutic option especially for patients with multiply relapsed/refractory cHL and perhaps other hematological malignancies expression CD25.

In recent years, significant advances have been made in the management of r/r HL with the introduction of the anti-CD30 antibody-drug conjugate (ADC) brentuximab vedotin (BV) and the anti-PD1 checkpoint inhibitors (CPI) nivolumab and pembrolizumab. Additionally, promising new therapeutics are emerging, such as CD25-directed ADC therapy and CD30-directed chimeric antigen receptor (CAR) T cells. While no consensus guidelines exist for the management of HL patients refractory to BV and checkpoint blockade, potential novel strategies and therapeutics are currently under investigation in hopes of expanding the treatment landscape for this challenging patient population.

The trial was terminated during dose escalation due to programmatic reasons other than safety. Hence, recommended dose was not determined.

While Treg modulation was seen with all populations, these data support further study, particularly of the Cami 45 µg/kg dose for pts with HL. Given that CD25 is the cognate target of Cami, these data suggest pts with HL achieving CR have higher drug exposure, resulting from lower baseline sCD25, and potential association with lower tumor burden. Although exposure at the 45 µg/kg dose showed moderate inter-patient variability, it was associated with noteworthy, cycle-related modulation in circulating Treg and clear increases in Teff:Treg ratios, thought to favor clinical response.

Methods : The LEOPARD trial was a phase II, multi centre, open label, single arm study of RAP maintenance after a single melphalan conditioned (200mg/m2) ASCT as part of up-front therapy. Subsequently, durable responses to post-ASCT lenalidomide maintenance were associated with a cytotoxic, controlled immune response whereas early relapse was characterised by a more uncontrolled inflammatory response and the emergence of B-reg-like cells prior to relapse. We conclude that immune profiling at baseline and after initiation of therapy may help to predict a more sustained response to lenalidomide maintenance enabling pre-emptive tailored treatment decisions.

The most advanced of these is AMG 420, which showed significantly improved response rates in relapsed/refractory multiple myeloma (MM) patients...Collectively, these findings demonstrate that the simultaneous T cell redirection and tumor-specific checkpoint inhibition with the LocATE leads to an improved therapeutic index with robust tumor cell killing and low levels of cytokine release. Capable of counteracting adaptive immune resistance caused by increased PD-1/PD-L1 signaling, the LocATE antibody has the prospect to significantly improve survival for multiple myeloma patients.

Synergistic anti-tumor activity was also demonstrated in a colorectal cancer model using CD25-ADC, a mouse-cross-reactive version of camidanlumab tesirine, in combination with gemcitabine. Altogether, these novel pre-clinical data warrant translation of the combination between camidanlumab tesirine and gemcitabine into the clinic.

Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.

Orthogonal evaluation of tumor-infiltrating lymphocytes (TILs) in solid tumors in mice and humans have identified CCR8, and several tumor necrosis family receptors (TNFRs), including TNFSFR8 (CD30), as receptors differentially upregulated on intratumoral Tregs compared to normal tissue Tregs and other intratumoral T cells, making these intriguing therapeutic targets.Brentuximab vedotin (BV) is approved for classical Hodgkin lymphoma (cHL) across multiple lines of therapy including frontline use in stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine. Interestingly, blockade of CD25 signaling prevents CD30 expression on T cell subsets without impacting proliferation, suggesting a link between CD25, the high affinity IL-2 receptor, and CD30 expression. Conclusions Together, these data suggest that BV may have an immunomodulatory effect through selective depletion of highly suppressive CD30-expressing Tregs.

Orthogonal evaluation of tumor-infiltrating lymphocytes (TILs) in solid tumors in mice and humans have identified CCR8, and several tumor necrosis family receptors (TNFRs), including TNFSFR8 (CD30), as receptors differentially upregulated on intratumoral Tregs compared to normal tissue Tregs and other intratumoral T cells, making these intriguing therapeutic targets.Brentuximab vedotin (BV) is approved for classical Hodgkin lymphoma (cHL) across multiple lines of therapy including frontline use in stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine. Interestingly, blockade of CD25 signaling prevents CD30 expression on T cell subsets without impacting proliferation, suggesting a link between CD25, the high affinity IL-2 receptor, and CD30 expression. Conclusions Together, these data suggest that BV may have an immunomodulatory effect through selective depletion of highly suppressive CD30-expressing Tregs.

Exceptional cases of BRAF p.V600E negative HCL do occur, and this highlights the diagnostic importance of integrated clinical, morphologic, and immunophenotypic findings. Additionally, while the small-molecule BRAF inhibitor vemurafenib has shown utility in patients with relapsed/refractory HCL, efficacy remains unknown in BRAF mutation-negative cases.

Cl-OCH3 also decreased expression of CD3+/CD4+/CD25+/FoxP3+ regulatory T cells and increased the Teff/Treg ratio. Therefore, the potent anti-cancer activities of NR4A1 antagonists are also accompanied by enhanced anti-tumor immunity in PD-L1-expressing triple-negative breast cancer and thus represent a novel class of drugs that mimic immunotherapy.

This study shows that a PBD dimer-based, CD25-targeted ADC is able to deplete T and eradicate established tumors via antitumor immunity. This represents a novel approach to efficiently deplete T via a very potent DNA damaging toxin known to induce immunogenic cell death. Moreover, this study provides proof of concept for a completely new application of ADCs as immunotherapeutic agents, as the main mode of action relies on the ADC directly targeting immune cells, rather than tumor cells. These strong preclinical data warrant the clinical evaluation of camidanlumab tesirine (ADCT-301), a PBD-based ADC targeting human CD25, either alone or in combination with checkpoint inhibitors in solid tumors with known T infiltration. A phase I trial (NCT03621982) of camidanlumab tesirine in patients with selected advanced solid tumors is ongoing.

Funding: ADC Therapeutics SA. Clinical trial identification: NCT03621982.

FP-1305 is a novel IgG4-antibody targeting CLEVER-1 and induces a phenotypic M2 to M1 immune switch of TAMs...Funding: Faron Pharmaceuticals LTD. Clinical trial identification: NCT03733990.

These include ADCT-301 (camidanlumab tesirine) and ADCT-402 (loncastuximab tesirine) in pivotal Phase 2 trials that contain the payload tesirine which releases the PBD dimer warhead SG3199...The level of resistance achieved was ~3000-fold for ADCT-301 and 3-fold for SG3199 in Karpas-299, and 8-fold for ADCT-502 and 4-fold for SG3199 in NCI-N87...These data show that acquired resistance to PBD-ADCs and SG3199 can involve specific ATP-binding cassette (ABC) drug transporters. This has clinical implications as potential biomarkers of resistance and for the rational design of drug combinations.

In patient-derived xenograft models of drug-resistant B-cell malignancies, treatment with a CD25-specific antibody drug-conjugate (ADCT-301) extended survival of transplant recipients or eradicated disease. These findings identified CD25 as previously unrecognized feedback regulator of oncogenic BCR-signaling and provide a rationale for therapeutic targeting of CD25 in refractory B-cell malignancies.

P1b, N=50, Not yet recruiting, ADC Therapeutics S.A.

22 pts with HL have been treated with doses ≥30 µg/kg, with an ORR of 63.6% (14/22) and a complete response rate of 27.3% (6/22); ORRs by prior treatment were: 13/21 (61.9%) pts who previously received brentuximab vedotin (BV), 10/16 (62.5%) pts who previously received a checkpoint inhibitor and BV and 5/11 (45.5%) pts who had prior stem cell transplant. In pts with R/R HL, active doses of Cami-T with acceptable safety profiles have been preliminarily identified during dose escalation and expansion of this study. The ORR in this heavily pretreated population is very promising and HL expansion cohorts are underway to better define the efficacy and safety of Cami-T. Dose escalation will continue to identify the MTD in NHL, with planned subtype-specific expansion cohorts at the MTD.