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Chimeric Antigen Receptor T cell therapy (CAR-T) is a gene therapy designed to harness the potency of antibodies and T-lymphocytes into one single medicine for the treatment of cancer. CAR-T therapy could be viewed as a “living anti-cancer drug” as the medicine itself consists of a living cell, which is genetically engineered as a pharmaceutical “chimera” to find and destroy cancer cells. The term chimera describes a monstrous being from Greek mythology composed from different animal parts. It appears in literature as a creature with two heads: a lion’s and a goat’s (see Figure 1 below). Like the creature from Greek mythology, a CAR-T medicine also has two heads: antibody binding domain and T-cell receptor (TCR) signaling domain.

Figure 1: According to Greek mythology, a Chimera was a hybrid with parts from different animals. It consisted of a lion with a goat’s head and a tail ending in snakes’ heads. In the Homer’s Iliad, a chimera is described as a “fearsome beast snorting out the breath of terrible flame of bright fire”.

Source – Chimera, Greek Mythology, www.mythortruth.com

In science, the term chimera is often used to describe hybrids from different species, such as a virus with DNA sequences from different species, or a CAR-T drug construct consisting of an antibody fused to a T lymphocyte, combining the medical potency of an anti-cancer antibody with the cancer killing properties of a T lymphocyte. (read Part 1 of the CAR-T article series here)

Hurdles Limiting Treatment of Solid Tumors

CAR-T cells are engineered to infiltrate the tumor mass and persist in it over long periods, which is required to kill cancer cells. However, objective tumor responses (tumor shrinkage) in solid tumors are frequently short-lived as the tumor microenvironment generate inhibitory signals rendering CAR-T cells inert. Inhibitory signals primarily come from a different type of T-lymphocytes known as “regulatory T cells” (Tregs), and from checkpoint molecules (CTLA-4, PD-1, LAG3, or TIM-3) expressed on the cell surface, which shut down CAR-T cells. When traditional CAR-T cells enter the tumor mass, they face physical and chemical barriers, they do not proliferate, are inhibited, and do not reach and kill cancer cells. These hurdles have been difficult to overcome. Another significant challenge for widespread adoption of CAR-T therapies is safety of these drugs. CAR-T treatment is associated with significant neurotoxicity and cytokine storms, which could be fatal in some treated patients.

Biotechnology Innovations in CAR-T Area

In recent years, significant advances in CAR-T technologies have been implemented by various companies in the biotechnology industry. Although there are still hurdles to overcome, especially to develop efficacious CAR-T candidate medicines for the treatment of solid tumors, the industry continues to innovate. Better knowledge of T-cell receptor functions, improved understanding of anti-cancer immunology and a wider industry participation on these endeavors should generate better results in CAR-T human clinical trials. Allogene, Sorrento, Cellectis, Bellicum, CRISPR Therapeutics and Celyad are among innovating companies in the CAR-T area (read Part 1 of the CAR-T article series here).

Allogene (Nasdaq: ALLO) is developing “off-the-shelf” CAR-T medicines for the treatment of both blood cancers and solid tumors. The Company’s lead drug is UCART19, targeting CD19, a cell surface protein expressed on B-cells, including cancerous B-cells. Through a gene editing process, Allogene knocks out the natural T cell receptor from CARs to avoid “graft versus host disease” (GvHD). The main challenge for allogeneic CARs is the fact that the host (patient) immune system will reject the injected CAR-T cells. Allogeneic CARs come from a donor with a different genetic makeup (MHC - Major Histocompatibility Complex Antigen) than the host. Thus, the host’s immune system recognizes the CARs as foreign cells and could potentially kill them. In order to overcome this, Allogene knocks out the CD52 gene in CAR-T cells rendering them resistant to anti-CD52 antibody treatment. Anti-CD52 antibody treatment can therefore be used to suppress the host immune system and allow Allogene’s CAR-T cells to stay engrafted to achieve maximum potential efficacy.

Sorrento Therapeutics (Nasdaq: SRNE) is developing a CAR-T targeting CD38, a tumor associated antigen (TAA) selectively expressed on the surface of cancer cells, for the treatment of multiple myeloma (a type of blood cancer). Given that CD38 is expressed selectively on the surface of cancer cells, but not on normal cells, CD38 CAR-T might show minimal on-target/off-tumor toxicity (toxicity due to recognizing the correct target on the surface of normal cells). In November of last year, Sorrento announced results from Phase I trials on the use of CAR-T drugs targeting carcinoembryonic antigen (CEA) and prostate-specific membrane antigen (PSMA) for the treatment of solid tumors. Sorrento administered the CAR-T treatment utilizing a unique “Pressure-Enabled Drug Delivery” (PEDD) manufactured by TriSalus™ Life Sciences. PEDD technology overpowers the high-pressure characteristic of solid tumors, which limits penetration of the tumor mass by therapeutic agents. Using PEDD delivery, the number of CAR-T cells increased within the tumor mass. In the trial, two out of 4 pancreatic cancer patients showed complete disappearance of the liver metastasis (all patients showed reduced CEA levels on tumor cells). Median overall survival (OS) was 8.3 months in treated patients compared to only 3-6 months observed with standard of care treatment (historical data). Safety is another advantage of PEDD CAR-T treatment as it avoids neurotoxicity and cytokine release syndromes observed with systemic delivery of CAR-Ts.

Cellectis (Nasdaq: CLLS) is developing allogeneic (“off-the-shelf”) CAR-T product candidates using gene editing of T-cells derived from healthy donors. Gene editing is performed using “transcription activator-like effector nuclease” (TALEN), a gene editing nuclease-based technology allowing very precise and targeted gene modifications to the CAR-T cells. Cellectis’ lead product is currently being developed for the treatment of CD19-expressing hematological malignancies such as acute lymphoblastic leukemia (ALL). Cellectis approach of using an allogeneic, frozen, “off-the-shelf” T-cell based medicinal product has the potential to overcome limitations experienced with autologous therapies, such as very high costs and difficult manufacturing logistics. At the American Society of Hematology (ASH) Meeting in December of 2018, Cellectis presented preliminary results from Phase I studies of UCART19. The data demonstrated an 82% complete remission rate in treated acute lymphoblastic leukemia patients.

Bellicum Pharmaceuticals (Nasdaq: BLCM) is developing two CAR-T candidate medicines: BPX-601 and BPX-603. BPX-601 is an autologous CAR-T product candidate engineered using Bellicum’s proprietary “activation switch technology”, which is designed to treat solid tumors expressing prostate stem cell antigen (PSCA). The use of Bellicum’s activation switch technology results in a higher number of CAR-T cells penetrating the tumor mass and attacking cancer cells. Bellicum’s CAR-Ts persist for a longer time in the tumor mass, which increases the efficacy of this cancer treatment. Furthermore, the activation switch technology triggers an anti-cancer immune response by the host, modulating the tumor microenvironment. All these features combined are designed to increase treatment potency relative to traditional CAR-T therapies. In a Phase I/II clinical trial, nine out of 17 (53%) PSCA-positive pancreatic cancer patients showed CAR-T cells persisting for more than three weeks in the tumor mass. In the trial, 62% of the evaluable patients (8/13) had stable disease and three patients showed tumor shrinkage of 10% to 24%.

Bellicum’s BPX-603 is a dual-switch CAR-T product containing both the “activation switch technology” and a “safety switch technology”. The safety switch technology programs CAR-T cells to commit suicide (apoptosis) if the treated cancer patient shows any symptoms of toxicity. The activation switch controls the potency and efficacy of the CAR-T, whereas the safety switch minimizes the treatment’s potential toxicity. Both switches are turned on by administering oral drugs to cancer patients. The activation switch is turned on by intake of the oral drug rimiducid, whereas the safety switch is turned on by rapamycin, another oral drug. Bellicum’s BPX-603 is the first controllable dual-switch CAR-T candidate medicine. It targets solid tumors that express the “human epidermal growth factor receptor 2 antigen” (HER2).

CRISPR Therapeutics (Nasdaq: CRSP) is developing CTX130 as an allogeneic CRISPR/Cas9 gene-edited CAR-T cell therapy targeting CD70 expressing cancers, including hematological (blood) and solid tumors. According to the medical literature, CRISPR/Cas9 gene editing is faster, cheaper and easier to use than competing gene editing systems such as “transcription activator-like effector nuclease” (TALEN), and zinc-finger nucleases (ZFNs).

Celyad SA (Nasdaq: CYAD) is developing a different type of chimera. Celyad’s CAR-T medicines consist of an engineered T lymphocyte with a TCR fused to the NKG2D receptor, which is normally found on the surface of natural killer (NK) cells. This chimera has also two heads: NKG2D receptor and TCR. It differs from traditional CAR-Ts on the replacement of the “antibody binding domain” by NKG2D receptor. Like T lymphocytes, natural killer cells have also the ability to destroy cancer cells. The advantage of using the NKG2D receptor over an antibody binding domain is that NKG2D binds to multiple tumor antigens, instead of only one antigen as it is the case for an antibody. Celyad believes that NKG2D chimeras will be more potent than traditional CAR-Ts for the treatment of cancer.

In summary, the consensus among academics and industry experts is that research and development in CAR-T area will intensify in coming years, fueled not only by the current success of Gilead and Novartis, but also by recent data with fourth generation CAR-T medicines. They expect more biotechnology companies jumping into the fray, as the industry copes with the challenges of treating solid tumors with anti-cancer cell therapies, and innovation in this area accelerates.

Sources:

“Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM)”. Cancers 2017, 9(9) p115

“Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy”. Molecular Therapy: Nucleic Acids Vol. 9 December 15, 2017.

“Programming CAR-T cells to kill cancer”. Nature Biomedical Engineering 2018, Vol 2, June 2018, p377-391

Switching on the green light for chimeric antigen receptor T-cell therapy. Clinical & Translational Immunology 2019, Vol 8, e1046

“CAR-T with License to Kill Solid Tumors in Search of a Winning Strategy”. International Journal of Molecular Sciences 2019, Vol 20, p1903

“Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities”. Oncotarget 2015, Vol 8(52), p90521-90531

“Two-Dimensional Regulation of CAR-T Cell Therapy with Orthogonal Switches”. Molecular Therapy - Oncolytics 2018 Dec 20;12:124-137

“Therapeutic potential of CRISPR/Cas9 gene editing in engineered T-cell therapy”. Cancer Medicine 2019, DOI: 10.1002/cam4.2257

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