Cancer treatment: back to the cytokines

Chicago. When you hear the concept of cancer immunotherapy, the first thing that comes to mind is checkpoint inhibition – and then perhaps also treatments with antibodies such as rituximab or with so-called CAR (chimeric antigen receptor) T cells against haematological neoplasia. One class of drugs from which the first approved immunotherapeutics came was a bit forgotten: cytokines.

Cytokines are proteins that occur naturally in many living things and are involved in almost all biological processes. In cancer, cytokines are relevant primarily because of their functions in cell proliferation and the immune system. Therefore, three types of cytokines are primarily important here:

Interferons (IFN): Various immunostimulatory signaling molecules, including e.g. IFN-α or IFN-γ;

Interleukins (IL): Immunostimulatory and pro-inflammatory signaling molecules, but also those that attenuate immune and inflammatory responses. They are numbered in the order in which they were discovered or described (such as IL-2, IL-17, etc.);

Colony Stimulating Growth Factors (CSF): They are primarily involved in the proliferation and maturation of bone marrow (hematopoietic) stem cells.

Biotechnologically produced forms of cytokines for cancer treatment were introduced in Germany as early as the 1980s, making them the very first approved cancer immunotherapies. It was IFN-α2a in hairy cell leukemia in 1987, with subsequent approval extensions to include treatment of Kaposi’s sarcoma, chronic myeloid leukemia (CML), non-Hodgkin’s lymphoma, renal cell carcinoma, and malignant melanoma. And that was IL-2 in 1989 for the treatment of metastatic renal cell carcinoma.

Overall, oncological cytokine treatments did not live up to the expectations placed on them – not least because their effect was often in a particularly unfavorable relationship with serious side effects. The therapeutic importance of cytokines therefore continues to decline with the availability of new treatment options. An exception is filgrastim (approved in 1991) and its derivatives, which as granulocyte CSF still help buffer bone marrow suppression due to oncological therapies.

Cytokine studies presented at ASCO

A large body of data presented at ASCO’s annual conference suggests that cytokines could also regain importance in the importance of immunotherapy. Most come from early clinical stages – but not only. Examples are:

Phase I / II study: Nemvaleukin alfa in different units:

Dr. Ulka N. Vaishampayan, University of Michigan Cancer Center, MI, presented preliminary data on nemvaleukin alfa. Nemvaleukin alfa is a synthetic cytokine that binds to specific IL-2 receptors (IL-2R) and is thought to induce T cells and natural killer cells (NK) to fight tumors. At the same time, the activation of immunosuppressive regulatory T cells (Treg) should be kept as low as possible. Nemvaleukin alfa was also designed not to activate certain IL-2R types in the first place; this promises that the drug will develop fewer side effects than if its natural model – IL-2 – was administered directly.

Results of the Phase I / II ARTISTRY-1 study [NCT02799095] had confirmed the hopes for efficiency and safety in general, Vaishampayan summed up. Overall, nemvaleukin alfa was well tolerated, therapy-related grade 3/4 toxicities occurred primarily as transient neutropenia; at the same time, cytokine-based therapy has shown promising efficacy in patients with various tumors, some of which have already been extensively treated.

Nemvaleukin alfa was evaluated as monotherapy in patients with clear cell renal cell carcinoma (RCC; n = 22) or melanoma (n = 46), both indications where some effect of IL-2 had been previously shown. The objective response rates (ORR) were 18.2% and 8.7%, respectively.

In another cohort, individuals with a variety of tumors (from Hodgkin’s lymphoma to ovarian cancer) were treated with a combination of nemvaleukin alfa and the checkpoint inhibitor pembrolizumab; here the ORR was 16.1% overall.

Vaishampayan highlighted that positive signals for nemvaleukin alfa had been seen in mucosal melanoma (ORR: 33.3%) and platinum-resistant ovarian cancer (ORR: 28.6%). Two follow-up studies are currently underway with these indications (Phase II study ARTISTRY-6 and Phase III study ARTISTRY-7.

Phase II / III study: IL-15R-oneFC in bladder cancer

If bladder cancer has not yet infiltrated any muscular parts of the bladder (NMIBC, “nonmuscle-invasive bladder cancer”), specific immunotherapy is the preferred treatment: Drip into the bladder, an attenuated form of bovine tuberculosis bacterium Mycobacterium bovis (BCG), Bacillus Calmette triggers an immune response that then fights the tumor cells.

If those affected do not respond to BCG therapy, the further procedure is not easy: Although surgical removal of the bladder would eliminate the carcinoma, it also leads to severe limitations in the quality of life, so a therapy goal in this situation is cystectomy, if possible. delay far. Data on a combined treatment of BCG and a specific cytokine complex – IL-15RaFc – by Dr. Karie Chamie, UCLA Health, Los Angeles. The role of IL-15RaFc is to further increase the immune stimulation of BCG by activating T cells and NK (without overstimulating immunosuppressive Tregs).

In fact, 71% of BCG refractory NMIBC patients with carcinoma in situ (CIS; n = 83) had a complete response to the combination of BCG plus IL-15RaFc with a median response time (DOR) of 26.6 months. Over a two-year period, 89% avoided cystectomy and 96% developed into muscle invasive carcinoma.

Chamie pointed out that the combined therapy as a local therapy not only had relatively few side effects, but also performed well in terms of efficacy in an indirect comparison with pembrolizumab monotherapy: For example, the rate of complete remissions (CR) in Phase II Study KEYNOTE -057, which used pembrolizumab mono in BCG refractory NMIBC, was 41% and median DOR was 16.2%.

Discuss Dr. Michiel Simon Van Der Heijden of the Holland Cancer Institute, Amsterdam, described the results of cytokine-assisted BCG therapy as “exciting” and “beneficial” compared to the KEYNOTE-057 study, but at the same time warned of the limitations of indirect study. comparisons. Regardless, he was also convinced of the potential of the combination of BCG plus IL-15RaFc: “I personally believe the approach is now ready to be tested in Phase III clinical implementation studies”.

Interferons are also left

Approaches aimed at making IFN useful for tumor therapy were also presented at the ASCO conference. An example is modakafusp alfa. The substance consists of two “disarmed” IFN-α-2b molecules that are genetically fused to parts of an anti-CD38 antibody. CD38 is particularly highly expressed by multiple myeloma cells, which is why modacafusp alfa has been tested for multiple myeloma for some time. The first results that are promising: The drug appears to have a direct antiproliferative effect on the myeloma cells and also indirectly and directly stimulate immune cells.

Because certain non-malignant immune cells also have CD38 on their surface, and because CD38 may also be important for the PD-1 / PD-L1-mediated “immunescape” from tumors, it is conceivable that modacafusp alpha may also have antitumor effects on others. devices. That this is in fact the case suggests early data from a phase I / IIb study in which patients with various metastatic solid tumors participated, including people with colorectal carcinoma or melanoma. Side effects have been manageable and modacafusp alpha treatment is now being further evaluated in phase II melanoma (in combination with pembrolizumab), reported Melissa Lynne Johnson of the Sarah Cannon Research Institute, Nashville, TN.

Back to the Future

In cytokine treatments, which are in the early clinical stages, there are still a number of critical issues that need to be clarified – for example with regard to DOR or cumulative or very rare toxicities. These and other points will need to be clarified in later research phases. Dr. Kim Allyson Margolin from St. John’s Cancer Institute in Santa Monica, CA. At the same time, using the example of modacafusp alfa, she praised the fact that innovative formulations could help make cytokines useful for antitumor therapy in the future, which would otherwise have a very adverse effect-side effect ratio.

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