In general, one avoids fighting on ground of the enemy’s choosing. But when the enemy is a solid tumor, one must do battle in the tumor microenvironment, a hostile terrain where one’s allies in the immune system may lose their way, exhaust themselves, or even switch sides, lending cancer cells aid and comfort. Fortunately, prominent allies—such as T cells, natural killer (NK) cells, and antigen-presenting dendritic cells—are being recruited, retrained, and “uparmed” by developers of cell-based antitumor therapeutics.

Several of these developers are discussed here. They’ve been interested in adding new, more potent products to the cell-based anticancer armamentarium. As this article indicates, several new products are already being evaluated in preclinical and clinical trials.

Bucking up tumor-infiltrating lymphocytes

“We spent a significant amount of time optimizing our manufacturing process, which initially took five to six weeks but currently takes 22 days and has a very high success rate,” says Maria Fardis, PhD, president and CEO of Iovance Biotherapeutics. The cell therapy platform at Iovance Biotherapeutics is built around the properties of tumor-infiltrating lymphocytes (TILs), immune cells that surround and infiltrate malignant tissues and are critical for immunosurveillance.

One of the mechanisms that impairs the function of TILs is the ability of cancer cells to evade detection. The technology developed at Iovance involves extracting TILs from the patient, stimulating them with IL-2, and expanding them in a process that optimizes their activation and eliminates the immune-suppressive environment. The cells are frozen and re-administered to the patient one week after the patient has undergone lymphodepletion.

“This is a highly personalized one-time therapy,” notes Fardis. The infused cells detect the chemokines produced by the tumor, exit the capillary bed, and bind tumor cells through several recognition elements. “Once recognition occurs,” she explains, “the cells lyse the tumor cells by multiple mechanisms, including direct killing by interferon gamma, granzyme B, and perforin.”

“We are going after cancers that have a high mutational load and present many new different antigens, which makes these cancers very difficult to treat with one drug,” Fardis continues. “This is why taking advantage of the immune system, which is capable of recognizing multiple antigens, provides the best option.”

Company-sponsored studies that are part of the Iovance clinical pipeline include an early Phase I trial for chronic lymphocytic leukemia and Phase II clinical trials for malignant melanoma, cervical cancer, head and neck cancers, and non-small-cell lung cancer.

In a Phase II trial of patients with metastatic melanoma with average target lesions over 10 cm and who attempted a mean of 3.3 therapies and progressed on at least one of those, 81% of the patients that received autologous TIL therapy had a reduction in the tumor burden.

“From a scientific perspective, cell therapies are here to stay,” declares Fardis. “Improving the infrastructure of hospitals to accept patients and facilitate these therapies will be really important to ensure their uptake.”

Squeezing antigen-presenting cells

“We use Cell Squeeze® to engineer antigen-presenting cells, the cells that naturally activate T-cell responses,” says Armon Sharei, PhD, CEO and founder of SQZ Biotech. The company’s proprietary Cell Squeeze platform is based on the discovery that squeezing cells through a constriction temporarily disrupts their membranes and allows the delivery of molecules. “This approach,” asserts Sharei, “solves a fundamental problem in a field where there have been relatively few things that people could make cells do.”

Cell Squeeze® platform
The Cell Squeeze® platform, from SQZ Biotech, uses microfluidics and high-speed deformation, or cell squeezing, to disrupt cell membranes and deliver a range of materials into numerous primary cell types while minimizing impacts on cell function and viability. For example, antigen-presenting cells may be engineered to present a desired antigen, potentially creating therapeutics for cancer and autoimmune disorders.

SQZ Biotech is developing applications for oncology and other areas, such as immunotolerance, which have not been adequately explored by other approaches. The flexibility of Cell Squeeze, in terms of the cargos that can be used and cell types that can be modified, provides opportunities to engineer antigen-presenting cells effectively and use them to stimulate T-cell responses, as shown by in vivo studies with mouse and in vitro studies with human cells.

“We see this as a much more patient-friendly format for cell therapy,” maintains Sharei. “It is also a lot simpler from a manufacturer perspective.”

In an ongoing Phase I trial, scientists at SQZ Biotech are dosing patients who have human papillomavirus (HPV)-positive tumors. “The goal is to demonstrate that our approach is safe and that we can generate a CD8 response that can target the tumors,” emphasizes Sharei. The protocol is different from previous cell therapy approaches not only because it is in a solid tumor context, but also because it does not require any preconditioning treatment. “We don’t expect the therapy to have significant toxicity,” says Sharei.

The company announced in January 2020 that for the first patient dosed, engineered autologous antigen-presenting cells designed to induce a CD8 T-cell response against HPV16 were manufactured in less than 24 hours. This sort of turnaround time is far shorter than the several weeks needed to generate chimeric antigen receptor (CAR) T cells. “We believe that if we can show benefits, we can very quickly apply this strategy to other tumor types,” Sharei states. “We only have to switch out the target that activates the CD8 T cells.”

Turning NK cells into “smart” weapons

“Because our technology does not involve genetic engineering or viruses, it facilitates easier and quicker research and drug development at lower costs,” says Sonny Hsiao, PhD, CEO, president, and co-founder of Acepodia. Acepodia’s ACC™ (Antibody-Cell Conjugation) platform bioconjugates tumor-targeting antibodies directly to the surface of oNK cells (off-the-shelf NK cells). These cells come from a proprietary human NK cell line that Acepodia mass produces under GMP conditions. The guiding system provided to NK cells allows them to target and lyse tumor cells.

ACC™ (Antibody-Cell Conjugation)
Acepodia’s ACC™ (Antibody-Cell Conjugation) technology directly links tumor-targeting antibodies to the surface receptors of the company’s proprietary human natural killer cell line (oNK cells). Antibody binding to the tumor antigen induces clustering and stimulation of cell surface receptors and the downstream activation of oNK cells. Once activated, oNK cells release cytotoxic granules that lyse and destroy tumor cells.

ACE1702, the lead clinical candidate at Acepodia, uses anti-HER2-conjugated oNK cells to target HER2-expressing solid tumors, including endometrial, ovarian, breast, and gastric cancers. The company received FDA

clearance for ACE1702 in January 2020 as an Investigational New Drug. “We will start Phase I trials at three medical centers in the United States,” informs Hsiao.

Another program, currently in preclinical stages, guides oNK cells toward PD-L1. It is being evaluated for use against melanoma, lung cancer, and head and neck cancers.

Allogeneic and autologous approaches

“The two main focus areas at Celyad involve developing the NKG2D [natural killer group 2, member D] receptor in the autologous and now the allogeneic setting and creating an allogeneic platform that can be used with any particular target,” says David Gilham, PhD, the company’s vice president of research and development. NKG2D, an activating NK cell receptor, can bind to eight different stress-induced ligands that are naturally expressed on 80% of hematological and solid cancer cells.

The lead and the first autologous candidate at Celyad, CYAD-01, engineers a patient’s T cells to express NKG2D. CYAD-01 targets cancer cells in the core of the tumor and in the tumor microenvironment and establishes long-term cellular memory against the tumor by inducing an adaptive immune response.

CYAD-01 is being evaluated in the THINK study, a Phase I trial of patients with metastatic colorectal cancer, ovarian cancer, and pancreatic cancer who did not respond to other treatments and did not receive preconditioning therapy. Early findings from THINK indicated that CYAD-01 was well tolerated as a standalone therapy and led to disease stabilization in 29% of the participants.

More recent findings from the THINK study showed that CYAD-01 had clinical benefits in patients with relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. In data presented at the American Society of Hematology (ASH) conference in December 2019, 8 out of 15 evaluable patients treated with CYAD-01 demonstrated antileukemic activity, including 5 out of 8 that exhibited an objective response.

Another Phase I trial, SHRINK, administered increasing doses of CYAD-01 together with a combination of leucovorin, fluorouracil, and oxaliplatin (FOLFOX) to colorectal cancer patients whose liver metastases may be surgically removed. At the Society for Immunotherapy of Cancer (SITC) Annual Meeting in 2019, of nine patients treated in the SHRINK study, six presented stable disease and one had a partial response.

A Celyad program in the allogeneic line, CYAD-101, the first of a family of non-gene-edited allogeneic CAR T-cell clinical programs, combines CYAD-01 with a T-cell receptor (TCR)-inhibiting molecule (TIM), a peptide that inhibits TCR signaling to decrease or eliminate the risk of graft-versus-host disease. In combination with the FOLFOX regimen, CYAD-101 is currently in a Phase I trial, called alloSHRINK, for patients with metastatic colorectal cancer. At SITC, encouraging antitumor activity was reported from the trial. Two patients achieved a confirmed partial response, and five patients achieved stable disease.

“In the most recent clinical program in the autologous setting that we just started, we combined the use of NKG2D cells with short hairpin RNA (shRNA) to control the target expression of the T cells,” says Gilham. As part of an exclusive agreement with Horizon Discovery Group for the use of its shRNA technology, Celyad started its next-generation autologous NKG2D-based CAR T-cell candidate, CYAD-02, which in preclinical models led to persistent antitumor activity.

Gilham specifies two key goals: First, improve autologous therapies. Second, develop CAR T-cell therapies in an allogeneic and much more straightforward manner. “Our hope,” he stresses, “is to avoid some of the challenges that are currently facing some of our colleagues in the cell therapy space.”

Making cell therapies easier, faster, and safer

“We are building regimens that are patient-centric, not product-centric,” says Barry J. Simon, MD, president and chief administrative officer of NantKwest. The company’s cell therapy strategy uses the proprietary NK-92 cell line together with an IL-15 cytokine and other immune activators. Collectively, these factors activate NK cells, dendritic cells, and T cells, allowing tumors to be attacked in a three-pronged manner.

natural killer (NK) cells
NantKwest technology modifies natural killer (NK) cells so that they may take any of several approaches to the destruction of cancer cells. For example, the company’s t-haNK product can avail itself of three modes of killing: innate killing, antibody-mediated killing, and chimeric antigen receptor–directed killing. The t-haNK approach is intended to be combined with therapeutic antibodies to effectively target either two different epitopes of the same cancer-specific protein or two different cancer-specific proteins.

The NantKwest manufacturing process has become fully insourced and integrated. After a master cell bank is expanded serially, cells are harvested, reconstituted, and frozen for future use. After the products are sent to clinical centers, they can be readily thawed and infused into patients over an hour. Patients are treated in outpatient settings, not in hospitals.

“We have transformed our cell therapy production process into a comparable but easier process than the one used to manufacture monoclonal antibodies,” asserts Simon.

NantKwest has generated ample preclinical research data. To validate this data, NantKwest collaborated with Jeffrey Schlom, PhD, a senior investigator at the National Cancer Institute (NCI) and head of the NCI’s Laboratory of Tumor Immunology and Biology. The NantKwest and the NCI have been working together for several years under a Cooperative Research and Development Agreement (CRADA). “The NCI,” Simon notes, “performed a substantial amount of in vitro and in vivo research and provided valuable feedback on our products.”

NantKwest currently manufactures two lead products. The first one, haNK, is a CD16, ERIL-2-enhanced NK cell line designed to be paired with a monoclonal antibody and other agents. The second product, PD-L1.t-haNK, is a human-derived allogeneic NK cell line engineered to express a CAR targeting PD-L1.

Because this second product also produces intracellular IL-2 for enhanced CD16-targeted antibody-dependent cellular cytotoxicity, it can be grown without cytokine supplementation. “The IL-2 is not secreted at any detectable levels, accounting for the lack of IL-2 toxicity seen to date,” reports Simon.

These two products catalyzed the development of a staged trial design, the Nant cancer vaccine. A streamlined version of this vaccine uses a tumor-conditioning agent, such as low-dose Abraxane (albumin-bound paclitaxel) or aldoxorubicin together with N-803, an IL-15 superagonist that stimulates NK- and T-cell function without inducing negative immune suppression. “We can combine this regimen with an antibody depending on what the disease is,” Simon points out.

This multipronged approach neutralizes the defense of the tumor microenvironment, stimulates NK cells as the first line of defense, facilitates the NK cell to dendritic cell to T cell cross-talking, initiates the engagement with the cancer cells, and causes their lysis. “All these mechanisms,” explains Simon, “are part of a very staged protocol that we have optimized over several years and that we tested on patients with different diseases.”

The use of PD-L1.t-haNK was authorized in a compassionate-use protocol for a patient with metastatic pancreatic cancer who had failed standard of care. After five infusions of PD-L1.t-haNK and N-803, the patient’s metastasis resolved completely, as shown by a CT/PET scan.

“We are not saying that this is a cure,” clarifies Simon, “but it is a remarkable outcome for this patient.” This was the first patient that received the PD-L1.t-haNK as part of a chemotherapy-free combination regimen. “When we put this in context with observed responses in our other clinical trials in this and other conditions, we have enough information to file registration trials,” declares Simon. “That is what we are currently doing for non-small-cell lung, pancreatic, and triple-negative breast cancer.”

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