The combination therapy against CD70 has demonstrated its potential

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The combination therapy against CD70 has demonstrated its potential

New insights into the role of CD70 in tumor progression further strengthen the rationale for harnessing CD70 in cancer patients with the potential to (1) specifically eliminate CD70 -expressing cancer cell populations and (2) eliminate tumor-promoting mechanisms through CD70-CD27 signaling axis, both in early and late disease.

Since CD70 expression is absent during steady state compared to CD27 , it has great potential as a cancer-specific target. It should be noted that activated T/B cells can transiently express CD70 , therefore, caution should be exercised when evaluating anti- CD70 approaches, as off-target effects remain a challenge.

Therefore, many promising therapeutic approaches targeting CD70 are being investigated in preclinical and clinical settings with the aim of improving treatment outcomes for cancer patients. Figure 1 shows an overview of all strategies that have completed or are undergoing clinical evaluation.

The combination therapy against CD70 has demonstrated its potential

Figure 1 Overview of ongoing and completed clinical trials of CD70-targeted drugs. Trials completed (solid line) and trials in progress (dashed line) were categorized according to study start date. Antibody-drug conjugate (ADC, blue); antibody (Ab, red); chimeric antigen receptor (CAR, green).

Antibody

Antibody-drug conjugates (ADCs) are monoclonal antibodies (mAbs) conjugated to cytotoxic agents that specifically bind to target proteins and internalize the cytotoxic agent, thereby killing tumor cells.

Several ADC compounds targeting CD70 have been developed and are undergoing clinical evaluation in hematological and solid cancers.

Four different ADCs entered the clinic, all of which have completed Phase I, with development of two compounds, AMG 172 (Amgen) and MDX-1203 (Bristol-Myers Squibb), discontinued.

While both SeattleGenetics’ ADC compounds (SGN-75 and SGN-CD70A) were discontinued from clinical trials due to toxicity, the company’s afucosylated monoclonal antibody, SEA-CD70, is currently being tested in patients with myeloid malignancies. Clinical evaluation of a phase I study (NCT04227847).

Although ADCs targeting CD70 are a promising approach to mediate selective killing of tumor cells, these drugs are dependent on the degree of internalization, which can vary widely between tumor types.

Another form of antibody-mediated therapy is based on antibody-dependent cellular cytotoxicity (ADCC), which relies on the activation of effector cells bearing the Fc receptor CD16 (FcyRIII) and binding to blocking target proteins.

The most typical Fc-bearing receptor effector cells that are activated upon binding are macrophages, although other effector cells such as NK cells, γδ T cells and dendritic cells also mediate ADCC.

Cusatuzumab (ARGX-110) is second only to complement-dependent cytotoxicity, enhancing ADCC properties due to increased binding to FcγRIIIa (due to afucosylation).

Its safety profile has been shown to be favorable, with no dose-limiting toxicities in patients with advanced solid and hematological malignancies.

In AML, cusatuzumab effectively eliminated LSCs in patients receiving hypomethylating drugs, while blocking the CD70-CD27 pathway induced AML blast and stem/progenitor differentiation.

One of the challenges for ADCC-dependent antibodies is the insufficient activation and function of immune effector cells, such as NK cells, because a large number of cancer patients have compromised immune systems.

CAR-T therapy

Chimeric Antigen Receptor (CAR)-T cell therapy utilizes a patient’s own T cells to better identify and eliminate a patient’s cancer cells by modifying these T cells to recognize tumor antigens in an HLA-independent manner.

CAR-T cell therapy has achieved great success in treating hematological malignancies, leading to FDA/EMA approval of CAR-T cell compounds targeting CD19: Kymriah (DLBCL, ALL), Yescarta (DLBCL, follicular lymphoma), Breyanzi (DLBCL), follicular lymphoma), Tecartus (CML) and Abecma (MM) [137].

In addition to different CAR-T therapies in preclinical development, there are currently 5 approaches based on anti-CD70 CAR-T, namely anti-hCD70 CAR (NCT02830724), 4SCAR70 (NCT03125577), CAR CD70 (NCT04662294), CTX130 (NCT04438083) and ALLO316 (NCT04696731), which are being evaluated in Phase I/II clinical trials in patients with hematological and solid malignancies, pending results on safety and efficacy in these different cancer types.

Despite its success in hematological malignancies, the treatment of solid tumors with this therapeutic modality remains challenging due to multiple obstacles, such as transport of metastatic cells to the tumor site, tumor penetration, and maintenance of viability [138] ].

Combined protocols evaluated in clinical settings

Combination regimens with CD70-targeting agents have been explored in clinical settings for certain cancer types.

Preclinical studies have shown that azacitidine, a hypomethylating agent (HMA), upregulates CD70 on AML LSCs, making these malignant cells more susceptible to CD70 targeting.

Based on these preclinical findings, a Phase I/II study was initiated combining cusatuzumab with azacitidine in previously untreated elderly patients with AML or high-risk myelodysplasia (NCT03030612).

Preliminary results from Phase I/II dose escalation showed hematologic response in 67% (8/12) of all patients with complete remission and complete remission and incomplete blood count recovery in 17% (2/12) of patients.

In addition, no dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached.

These promising results led to a randomized phase II trial in newly diagnosed AML patients who were ineligible for intensive chemotherapy combining azacitidine with cusatuzumab at 10 mg/kg or 20 mg/kg (NCT04023526).

Another promising regimen that has recently entered the clinic is the combination of cusatuzumab and venetoclax (+/- azacitidine) (NCT04150887).

BCL-2 plays an important role in the survival and persistence of AML blasts by sequestering pro-apoptotic BAX. Venetoclax is a selective inhibitor of BCL-2, which leads to the release of BAX, which leads to the permeabilization of the mitochondrial outer membrane, which leads to the apoptosis of LSCs.

Although venetoclax has shown promising activity in elderly or chemotherapy-inappropriate AML patients, successful elimination of all LSCs remains a major challenge for effective treatment of AML.

Similar to venetoclax, anti-CD70 therapy targets AML LSCs, but through different mechanisms, namely inhibition of LSC proliferation, stimulation of their differentiation into myeloid cells, and effector function-mediated cell killing [135].

Therefore, combining two complementary drugs targeting AML LSCs can produce additive/synergistic antitumor effects, thereby minimizing drug resistance. Preclinical data have demonstrated this synergistic effect of cusatuzumab and venetoclax (+/-HMA) on LSC [143].

Finally, cusatuzumab in combination with radiation and/or chemotherapy was evaluated in a phase I study in patients with nasopharyngeal carcinoma (NCT02759250).

Compared with the patient cohort who received monotherapy, patients who had received radiation and/or chemotherapy had longer progression-free survival, but it should be noted that the size was too limited for any conclusive statement [144].

There are currently no new clinical trials evaluating the combination of anti-CD70 therapy with chemotherapy or radiation in solid cancers.

Combination therapy of CAR targeting CD19 and CD70 has entered the clinic for patients with relapsed/refractory B-cell malignancies after chemotherapy (NCT03125577, NCT04429438).

Although clinical studies are still ongoing, preliminary results from patients with refractory and relapsed primary CNS lymphoma demonstrate long-term disease-free survival without inducing severe cytokine release syndrome and CART cells Associated encephalopathy syndrome.

The combination therapy against CD70 has demonstrated its potential

Figure 2 CD70-CD27 axis and tumor microenvironment.

Combined protocols evaluated in preclinical settings

In addition to combinations of CD70-targeted therapies that have entered the clinic, other innovative options are being explored in the preclinical setting.

One of these studies explored the combination of anti-CD70 therapy and a tyrosine kinase inhibitor targeting BCR-ABL1 in CML.

Here, the BCR-ABL1 kinase is constitutively active in the majority of CML patients, and tyrosine kinase inhibitors targeting the oncogenic product BCR-ABL are an effective therapeutic strategy in CML patients [146].

However, similar to AML, disease-induced LSCs pose a major challenge to the treatment of CML due to the persistence of drug-resistant LSCs.

The tyrosine kinase inhibitor imatinib was found to mediate gene expression changes in SP1 (up-regulated) and DNMT1 (down-regulated), resulting in demethylation of the CD70 promoter in CML cells, thereby upregulating CD70 expression in CML cells and Compensatory Wnt signaling [45].

In this study, the authors show that dual targeting of BCR-ABL1 and CD70 synergistically eradicates CML LSCs as more effectively prevents Wnt pathway activation and makes CML LSCs more susceptible to cell killing by anti-CD70 immunotherapy [45] .

Thus, dual targeting of BCR-ABL1 and CD70 eliminates LSCs and may overcome treatment resistance.

Different studies report an interesting combination of CD70-targeted therapy with chemotherapy.

In NSCLC, cisplatin treatment was shown to increase CD70 expression at the mRNA and protein levels.

Interestingly, the combination of cisplatin and the anti-CD70 drug cusatuzumab resulted in synergistic killing of NSCLC cell lines in vitro [101].

In ovarian cancer, CD70 expression on tumor cells correlates with clinical resistance to cisplatin [85].

Here, the authors show that antibodies targeting CD70 can inhibit the proliferation of drug-resistant tumor cells.

Therefore, combining chemotherapy and therapy with anti-CD70 antibodies can be used to overcome resistance to chemotherapy.

Finally, radiotherapy, similar to chemotherapy, was shown to increase membrane CD70 expression in gliomas, leukemias, and lymphomas [35, 147, 148].

Therefore, a combined strategy of anti-CD70 antibody and chemotherapy/radiotherapy can make malignant cells more susceptible to CD70-targeted therapy.

In conclusion

A combination approach with anti-CD70-targeted therapy has demonstrated its potential in preclinical and clinical settings.

So far, single and combination therapies have primarily been explored in AML, but other tumor types may also benefit from this approach.

Research in this area has led to greater understanding of the molecular mechanisms underlying the tumor-promoting and immune evasion roles of the CD70-CD27 axis in oncology.

Therefore, in addition to existing approaches that focus on targeting CD70, strategies to inhibit signaling pathways involved in the CD70-CD27 axis may become promising novel therapeutic alternatives in the future.

Further preclinical studies and clinical evaluation of CD70 targeting strategies will provide new insights into the mechanisms and roles of CD70 and may pave the way for new therapeutic options in oncology.

Reference:
https://doi.org/10.1186/s13046-021-02215-y

The combination therapy against CD70 has demonstrated its potential

(source:internet, reference only)

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