Meaningful Presentations at the Annual Meeting of the American Association for Cancer Research (AACR)
NKTR-214 Drug Improves Survival and Extends Immunity in cancer Immunotherapy
Nektar Therapeutics (NKTR) investigational immune-stimulatory cytokine therapy NKTR-214 is in Phase 1/2 trial. At the Annual Meeting of the American Association for Cancer Research (AACR) meeting, Nektar announced new preclinical data for NKTR-214, which demonstrate both its activity as a single-agent and its synergistic activity with checkpoint blockade.
The combination of NKTR-214 and a checkpoint inhibitor resulted in dramatically higher increases in anti-tumor T cell clonality and T cell tumor infiltration (TIL) as compared to dual checkpoint inhibition. The results were extremely encouraging as the combination with the immune checkpoint protein inhibitor demonstrate increased CD8-positive effector T cell function against the specific tumor and the concomitant presence of both tumor-infiltrating lymphocytes (TILs) clonality and infiltration, which significantly correlate with clinical response and better cancer patients’ survival outcomes.
In a CT26 colon carcinoma model, NKTR-214 as a single-agent led to superior increases in TIL clonality and infiltration as compared to either anti-CTLA-4 or anti-PD-1 therapy alone.
The combination of NKTR-214 with either mode of checkpoint inhibition led also to superior increases in both TIL clonality and infiltration relative to the combination of CTLA-4 and PD-1 inhibitors. The highest increases occurred when NKTR-214 was added to an anti-PD-1 therapy.
The addition of NKTR-214 to either an anti-CTLA-4 or anti-PD-1 agent could improve T cell clonality differences over checkpoint blockade therapies.
NKTR-214 is an investigational CD122-biased agonist currently in Phase 1/2 clinical development. The drug is designed to stimulate the patient’s own immune system to kill tumor cells by preferentially activating production of specific immune cells which promote tumor killing, including CD8-positive T cells and Natural Killer (NK) cells, within the tumor micro-environment.
CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these types of T cells.
In the preclinical studies conducted in multiple established tumor models presented at AACR, NKTR-214 demonstrated activity as both a single-agent and when co-dosed with either an anti-PD-1 agent or an anti-CTLA-4 agent. In a tumor re-challenge study conducted in an EMT6 colon carcinoma model, sequential dosing of anti-CTLA-4 followed by NKTR-214 resulted in durable immunity, with complete responders resisting a tumor re-challenge. Following a second re-challenge, 100% of the animals remained tumor-free without additional treatment.
Steve Doberstein, PhD, Senior Vice President and Chief Scientific Officer of Nektar Therapeutics said, “Our latest preclinical findings continue to show that treatment with NKTR-214 either as a single-agent or in combination with checkpoint blockade is superior to single or dual checkpoint inhibition in multiple models. The new data emphasize the cellular mechanisms underlying the remarkable efficacy of NKTR-214 in our preclinical models of cancer.”
The data presentation at AACR entitled, “Durable antitumor activity of the CD122-biased immuno-stimulatory cytokine NKTR-214 combined with immune checkpoint blockade,” can be accessed at: http://www.nektar.com/product_pipeline/oncology_nktr-214.html
About the NKTR-214 Phase 1/2 Clinical Study
A Phase 1/2 clinical study is underway to evaluate NKTR-214 in patients with advanced solid tumors.
The first stage of the study, which is expected to be complete in the second half of 2016, is evaluating escalating doses of single-agent NKTR-214 treatment in approximately 20 patients with solid tumors.
The primary objective of the first stage of the study is to evaluate the safety and efficacy of NKTR-214 and to identify a recommended Phase 2 dose. In addition, the study will also assess the immunologic effect of NKTR-214 on tumor-infiltrating lymphocytes (TILs) and other immune cells in both blood and tumor tissue, and it will also include TCR repertoire profiling. Dose expansion cohorts are planned to evaluate NKTR-214 in specific tumor types.
WOW. NKTR-214 is bringing increasing hope for cancer patients, as its use in combination with immune checkpoint protein inhibitors such as Opdivo and Keytruda or anti-CTLA-4 drug demonstrated a sustained improvement in the outcome of the immunotherapy treatments. The preclinical results are very promising and the drug is now being investigated in Phase 1/2 trials.
The NKTR-214 clinical study is being conducted initially at two primary investigator sites: MD Anderson Cancer Center under Drs. Patrick Hwu and Adi Diab; and Yale Cancer Center, under Drs. Mario Sznol and Michael Hurwitz.
Patients and physicians interested in the ongoing NKTR-214 Study can visit the “Clinical Trials” section of:
MD Anderson at: www.mdanderson.org using identifier 2015-0573
This is great news for cancer patients, their oncologists and Nektar Therapeutics
Advances in the Antibody Drug Conjugate in Cancer Treatment
Seattle Genetics is alive and in good health and is constantly improving its innovative antibody-based therapies for the treatment of cancer. Seattle Genetics develops antibody-drug conjugates (ADCs), capable of delivering cell-killing agents directly to cancer cells. The company’s lead product, ADCETRIS® (brentuximab vedotin), is a CD30-targeted ADC that, in collaboration with Takeda Pharmaceutical Company Limited, is commercially available in more than 60 countries. Additionally, ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials in CD30-expressing malignancies.
Seattle Genetics is also advancing vadastuximab talirine (SGN-CD33A; 33A) — an ADC expected to advance into a phase 3 trial for acute myeloid leukemia in 2016. Beyond Adcetris and 33A, the firm’s pipeline includes drugs in more than 22 clinical trials some are in final phases. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including AbbVie, Agensys (an affiliate of Astellas), Bayer, Genentech, GlaxoSmithKline and Pfizer.
At the 2016 AACR Meeting
At the AACR in New Orleans, Seattle Genetics (SGEN) highlighted novel antibody-drug conjugate (ADC) technology. The data selected in multiple presentations demonstrate the company’s relentless innovation in the field of ADCs. The innovation comprised the Seattle Genetics new auristatin-based drug-linker and other novel stable linkers believed to enable application of previously inaccessible cytotoxic payloads; Novel synthetic cell-killing payloads and the progress in understanding the chemical and biological properties of ADCs to inform potential future development.
ADCs are monoclonal antibodies designed to deliver cytotoxic agents selectively to tumor cells. Seattle Genetics’ linker systems are designed to be stable in the bloodstream and release the potent cell-killing agent inside the targeted cancer cells, thus, sparing the healthy cells, which reduces many of the toxic adverse effects of traditional chemotherapy while enhancing antitumor activity.
Multiple oral and poster presentations are being featured at AACR that highlight Seattle Genetics’ ADC technology advances. The firm’s presented abstracts include the following:
– Three posters that highlight the role of the tumor microenvironment in ADC clearance, antitumor activity and uptake. Importantly, preclinical data demonstrate the potential for tumor associated macrophages to contribute to antitumor activity through release of MMAE.
– The development of novel quaternary ammonium linkers for the stable conjugation and efficient release of tertiary amine-containing payloads
Preliminary data demonstrate that this technology enables the evaluation of drug classes previously inaccessible as ADCs, including auristatin E and tubulysin.
– The development of a novel methylene-alkoxy-carbamate (MAC) linker that enables direct conjugation of drugs through alcohol functional groups will be presented today, April 19, 2016 in an oral presentation (Abstract #4334).
This linker has the potential to expand the types of payloads utilized in ADCs.
– Data from a novel monomethyl auristatin E (MMAE) linker technology will also be highlighted today in a poster presentation
By incorporating a short polyethylene glycol (PEG) unit, a self-hydrolysing maleimide and a glucuronidase release mechanism, the new MMAE drug-linker demonstrates pronounced activity with an increased therapeutic index in preclinical models.
Antibody drug conjugate (ADC) will continue to play an increasingly incredible role in cancer treatment. We are witnessing the importance of Seattle Genetics’ approved ADC drug Adcetris in the treatment of classical Hodgkin lymphoma (HL) at high risk of relapse or progression and as consolidation treatment following autologous hematopoietic stem cell transplantation. We are also observing how another ADC drug, Kadcyla, from ImmunoGen (IMGN) is being upgraded in the treatment of HER2 positive breast cancer and is currently being used in combination with novel immunotherapy drugs.
As we observed in the AACR posters’ presentations, Seattle Genetics is constantly improving every component of its conjugated antibody products, from the antibody itself, to the linkers and the toxic loads. The pipeline is extremely rich with products aimed at various cancers. The attracted alliances are high caliber pharmaceutical and biopharmaceutical firms, with cannot be all wrong being attracted to Seattle Genetics ADC drugs.
Regarding acquisition, we believe SGEN represents a good opportunity for the large pocketed firms that seek to consolidate their oncology programs. We are experiencing a huge change in the treatment of cancer based on the increasing need for combination drugs after the surfacing and successes of immunotherapy drugs and approaches that have combination with various drugs in hundreds of clinical trials around the world.