acimtamig (AFM13)

P2, N=108, Completed, Affimed GmbH | Active, not recruiting --> Completed

Targeted therapies, including the antibody drug conjugate, camidanlumab tesirine, and transcriptional agents such mammalian target of rapamycin and histone deacetylase inhibitors have shown some potential in patients with refractory disease. Clinical trials with cellular therapies, including chimeric antigen receptor T cells targeting CD30 and allogeneic natural killer cells combined with AFM13, a CD30/CD16a-bispecific antibody, have shown promising results. The availability of more therapeutic options for this patient population is eagerly awaited.

AB-101 has demonstrated potent killing of tumor cell lines in vitro and in vivo, and preliminary results of a Phase 1/2 trial of AB-101 alone and in combination with rituximab in patients with R/R B cell non-Hodgkin lymphoma demonstrated AB-101 is well tolerated (Khanal et al...Patients aged ≥18 years are planned for enrolment and patients with R/R HL must have received at least two prior lines of therapy including prior combination chemotherapy, brentuximab vedotin (BV) and a checkpoint inhibitor...A run-in phase will assess two dose levels of AFM13 and AB-101 in 4 cohorts (Figure). A standard lymphodepletion regimen of fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day) will be administered IV from Day −5 to Day −3 at the start of each treatment cycle...In addition, an exploratory cohort (cohort 5) will begin enrolment of patients with CD30+ PTCL. Disease and efficacy assessments will be conducted at screening and on Day 43 (± 3 days) of each cycle.

Pts ages 15–75 with CD30+ lymphomas refractory to brentuximab vedotin were enrolled...Each treatment cycle consisted of fludarabine/cyclophosphamide (days −5 to −3) followed by infusion (day 0) of the AFM13-precomplexed CB NK cells, cultured for 14 days as described above, and three weekly IV infusions of AFM13 (200 mg, days 7, 14 and 21)... CB-derived cytokine-induced memory-like NK cells precomplexed with AFM13 have excellent tolerability and activity for pts with heavily pretreated and refractory CD30+ lymphoma.

P2, N=154, Recruiting, Affimed GmbH | Not yet recruiting --> Recruiting

P1/2, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Apr 2024 --> Apr 2025

P2, N=154, Not yet recruiting, Affimed GmbH

A total of 108 patients (age 21–93; 61% male; mean prior lines was 2.7, [46.3% with brentuximab vedotin]) were enrolled; PTCL subtypes assessed were PTCL not‑otherwise‑specified, angioimmunoblastic T cell lymphoma (AITL), anaplastic large cell lymphoma, other. AFM13 continues to show robust single agent activity and a well-managed safety profile in patients with PTCLrefractory to standard therapy. The ORR is comparable to therapies approved for this indication, and subgroup analysis from this study suggests potential patient characteristics which may predict a more favorable response to AFM13. These data support further clinical development of AFM13, including in combination with allogeneic NK cells, to augment the innate immune response to CD30 + tumors.

Patients had received a mean of 2.7 prior treatment lines; 46.3% received prior brentuximab vedotin (BV), 17.6% received prior auto-transplant. AFM13 monotherapy demonstrated robust clinical activity in heavily pretreated patients with R/R PTCL. The safety profile of AFM13 was well managed and consistent with previously reported data from prior and ongoing clinical studies with AFM13. These data support future evaluation of AFM13 in combination with other immunotherapies, including allogeneic NK cells, to further potentiate anti-tumor immune responses to CD30+ lymphomas.

P1/2, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Based on our data we hypothesize that CD16A shedding facilitates AFM13 induced ADCC potential of NK cells by allowing potent migration to distantly located tumor cells and serial killing. Especially in the context of AFM13 primary indications, Hodgkin and peripheral T cell lymphoma, migration of NK cells might have a particularly strong impact when treating cancer patients due to the disseminated nature of the disease.

Patients received a mean number of 2.7 prior treatment lines; 46.3% received prior brentuximab vedotin (BV), 17.6% received prior auto-transplant. AFM13 monotherapy was well managed and showed robust clinical activity in selected R/R PTCL subtypes. These data, together with encouraging preliminary efficacy seen in AFM13 combination studies in HL, support further evaluation of AFM13 in combination with NK cells to augment the innate immune response to CD30+ tumors.

Patients aged 15–75 years with R/R CD30+ lymphomas refractory to brentuximab vedotin are enrolled...Each treatment cycle consisted of fludarabine/cyclophosphamide (days −5 to −3), followed by infusion of the AFM13-NK cells, cultured for 14 days as described above (day 0), and three weekly IV infusions of AFM13 (200 mg, days 7, 14 and 21)... This is the first clinical trial to date using an ICE® construct precomplexed with cytokine-induced memory-like CB-NK cells to treat patients with CD30+ R/R HL and NHL. Our preliminary results indicate that this ICE® precomplexed CB-NK cell therapy has an excellent tolerability profile and is highly active in patients with heavily pretreated R/R CD30+ lymphomas and warrants further investigation.

In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2-28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life.

P1/2, N=30, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2023 --> Apr 2025 | Trial primary completion date: Apr 2023 --> Apr 2024

P1/2, N=30, Recruiting, M.D. Anderson Cancer Center | Phase classification: P1 --> P1/2

According to preliminary results from a phase I/II trial, cord blood-derived natural killer cells complexed with AFM13, a bispecific antibody, showed efficacy in patients with relapsed/refractory CD30+ lymphomas. Complete responses were seen, and treatment was extremely well tolerated.

No abstract available

Pts receive 2 cycles of fludarabine/cyclophosphamide (days −5 to −3) followed by AFM13-CB NK cells (day 0) and 3 weekly intravenous infusions of AFM13 (200 mg, days 7, 14 and 21). In conclusion, the preliminary results of this first clinical trial of ICE®-precomplexed NK cells for R/R CD30+ lymphoma indicate excellent tolerability and high activity and warrant further investigation of this approach. >

P2, N=145, Active, not recruiting, Affimed GmbH | Recruiting --> Active, not recruiting | Trial completion date: Feb 2023 --> Dec 2023 | Trial primary completion date: Apr 2022 --> Dec 2022

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.

Early clinical studies with AFM13 have demonstrated safety and efficacy, both as mono- and combination therapy with an anti-PD-1 checkpoint inhibitor (pembrolizumab) (Bartlett, N.L. et al., Blood 2020;136(21):2401–2409), in patients with relapsed or refractory (R/R) HL or peripheral T cell lymphoma (PTCL). More importantly, these assays demonstrate that the high ADCC potency and efficacy of NK cells, pre-complexed with CD16A-specific tetravalent ICE®, is maintained after one freeze-thaw cycle. These data suggest that high-affinity pre-complexing of adoptive NK cells with bispecific, CD16A-selective ICE® could be a novel cryopreserved off-the-shelf NK cell product for the effective depletion of tumor cells without the limitations and potential risks associated with the CAR-NK cell technology.

Early clinical studies with AFM13 have demonstrated safety and efficacy, both as mono- and combination therapy with an anti-PD-1 checkpoint inhibitor (pembrolizumab) (Bartlett, N.L. et al., Blood 2020;136(21):2401–2409), in patients with relapsed or refractory (R/R) HL or peripheral T cell lymphoma (PTCL). More importantly, these assays demonstrate that the high ADCC potency and efficacy of NK cells, pre-complexed with CD16A-specific tetravalent ICE®, is maintained after one freeze-thaw cycle. These data suggest that high-affinity pre-complexing of adoptive NK cells with bispecific, CD16A-selective ICE® could be a novel cryopreserved off-the-shelf NK cell product for the effective depletion of tumor cells without the limitations and potential risks associated with the CAR-NK cell technology.

We identify AFM13 as a promising combination with cytokine-activated adult blood or cord blood NK cells to treat CD30+ hematologic malignancies, warranting clinical trials with these novel combinations.

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.

P2, N=23, Completed, University of Cologne | Active, not recruiting --> Completed | Trial completion date: Dec 2021 --> Jul 2020

The median number of prior therapies was 4 (1-11) and 4 subjects had progressed on brentuximab vedotin. In addition, biological changes in NK infiltration and activation in the PB and tissue biopsy correlated with response. These data are the first to demonstrate that innate cell engagers modulate NK and T cell populations in the peripheral blood and tumor from patients and to determine that such changes are associated with patient benefit.

INTRODUCTION: The outcome of patients (pts) with classical Hodgkin Lymphoma (cHL) experiencing relapse after high dose chemotherapy, brentuximab vedotin (BV) and anti-PD1 antibody (Ab) treatment is poor and in most patients the duration of the response to this treatment is rather short. Treatment with AFM13 was well tolerated and showed modest activity in heavily pretreated pts. The responses documented in arm C qualified this arm with continuous AFM13 application over 5 days for further evaluation in trial stage 2 and thus indicated its potential. However, the trial was prematurely stopped due to low recruitment leading to the conclusion that the acceptance of the application schedule is extremely important.

Introduction: The outcome of patients (pts) with classical Hodgkin Lymphoma (cHL) experiencing relapse after high dose chemotherapy, brentuximab vedotin (BV) and anti-PD1 antibody (Ab) treatment is poor. Treatment with AFM13 was well tolerated and showed modest activity in heavily pretreated pts. However, the trial was prematurely stopped due to low recruitment leading to the conclusion that the acceptance of the application schedule is extremely important, especially in pts with multiple relapses.

Introduction: The outcome of patients (pts) with classical Hodgkin Lymphoma (cHL) experiencing relapse after high dose chemotherapy, brentuximab vedotin (BV) and anti-PD1 antibody (Ab) treatment is poor. Treatment with AFM13 was well tolerated and showed modest activity in heavily pretreated pts. However, the trial was prematurely stopped due to low recruitment leading to the conclusion that the acceptance of the application schedule is extremely important, especially in pts with multiple relapses.

Introduction: The outcome of patients (pts) with classical Hodgkin Lymphoma (cHL) experiencing relapse after high dose chemotherapy, brentuximab vedotin (BV) and anti-PD1 antibody (Ab) treatment is poor. Treatment with AFM13 was well tolerated and showed modest activity in heavily pretreated pts. However, the trial was prematurely stopped due to low recruitment leading to the conclusion that the acceptance of the application schedule is extremely important, especially in pts with multiple relapses.

Introduction: The outcome of patients (pts) with classical Hodgkin Lymphoma (cHL) experiencing relapse after high dose chemotherapy, brentuximab vedotin (BV) and anti-PD1 antibody (Ab) treatment is poor. Treatment with AFM13 was well tolerated and showed modest activity in heavily pretreated pts. However, the trial was prematurely stopped due to low recruitment leading to the conclusion that the acceptance of the application schedule is extremely important, especially in pts with multiple relapses.

P1, N=30, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation. This Phase 1b study was registered at www.clinicaltrials.gov as NCT02665650.

To overcome impaired antigen presentation, antibody-based cytotoxic strategies, namely antibody-drug conjugates (polatuzumab vedotin and brentuximab vedotin) and bispecific T-cell or NK-cell engagers (blinatumomab, REGN1979, RG6206, and AFM13), have rapidly evolved with promising clinical activity. As additional tools become available for lymphoma treatment, formulation of safe, rational combination strategies to combine them with standard therapy will be of paramount importance. A successful approach to the treatment of lymphoma may require both an optimized anti-tumor immune response as well as effective depletion of malignant lymphoid cells.

Eligible PTCL patients must have received at least 1 prior line of systemic therapy and, if diagnosed with systemic anaplastic large cell lymphoma, must have failed or be intolerant to brentuximab vedotin. ClinicalTrials.gov identifier: NCT04101331. Research Funding: Affimed GmbH