A D V E R T I S E M E N T F E A T U R E

A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N T

Carisma Therapeuticswww.carismatx.com

Carisma drives CAR-M engineeredmacrophage cancer therapy forwardCarisma Therapeutics is developing unique CAR macrophage therapies to treat solid tumors.The company’s lead CAR-M program, CT-0508, is ready to enter phase 1 testing.

Carisma Therapeutics is developing a unique, dif-ferentiated immuno-oncology (IO) treatment forsolid tumors based on chimeric antigen receptormacrophages (CAR-M). Current IO treatmentshave offered improved outcomes for some cancerpatients but leave behind many non-responders. Intumors that are ‘cold’ and lack infiltrating T cells,for example, checkpoint inhibitors tend to beineffective. CAR-T cells, engineered to recognizetumor-specific antigens, although successful insome blood cancers and lymphomas, have not beeneffective in solid tumors to date. To overcome thesehurdles, Carisma has developed CAR-M, leverag-ing the natural role of macrophages to initiate amulti-faceted innate and adaptive anti-tumorresponse. The company’s lead CAR-M program,CT-0508, will soon enter phase 1 testing, havingshown increased overall survival in a preclinicalmodel of HER2+ cancer.

Carisma’s CAR-M therapies rest on a break-through platform technology that enables geneticmanipulation of primary macrophages ex vivo andre-introduction into patients, enabling multipletherapeutic applications in and beyond oncology.CAR-M is an individualized therapy that beginswith isolation of primary monocytes from blooddrawn from a patient. The cells are then transducedwith the desired antigen-specific chimeric receptor,for example, anti-HER2, using proprietary viral ornonviral methods. The resulting CAR-M cells arecryopreserved and shipped back to the patient forreinfusion. Reinfused CAR-M are actively recruitedto tumor sites, with ~30% accumulating in tumorswithin 5 days in pre-clinical models. Like a Trojanhorse, CAR-M may be able to reach immuno-logically ‘cold’ tumors.

Once in the tumor, CAR-M are activated by tumor-associated antigen engagement with the CAR, sig-naling via CD3-ζ to phagocytose the tumor cell andrelease cytokines and chemokines that ‘warm up’the tumor microenvironment (TME). Virally trans-duced CAR-M are locked into a pro-inflammatoryM1 phenotype during the manufacturing process.They produce locally acting mediators that repro-gram the TME, drawing in T and natural killer (NK)cells, activating nearby antigen presenting cells(APCs), notably dendritic cells (DCs), and repolariz-ing tumor-associated macrophages (TAMs) towardan M1 phenotype. In addition to direct phagocytosisof tumor cells, CAR-M present a patient’s uniquearray of neoantigens to T cells, leading to a broadadaptive immune response that has the potential togenerate long-term immunity beyond the antigentargeted by the CAR (Fig. 1).

Promising lead candidateBased on impressive preclinical results, Carisma’slead candidate CAR-M therapy targeting HER2+cancers, CT-0508, is being rapidly advanced to theclinic, with investigational new drug (IND) approvalby the US Food and Drug Administration and phase 1start targeted for late 2020. HER2-specific CAR-Mwere tested in two xenograft models. In immuno-deficient mice injected with HER2+ ovarian can-cer (SKOV3) cells, a single HER2-specific CAR-Minjection improved overall survival, with 50% oftreated mice surviving to day 100 compared withloss of all control animals to cancer by day 60. Inimmunocompetent mice injected with CT26 HER2+

tumor cells, CAR-M shrank HER2+ tumors with a75% complete response rate and also showed activ-ity against a contralateral HER2- tumor, indicatingepitope spreading via T cell activation.

While targeted HER2+ cancer drugs have led toimproved survival in breast and gastric or gastro-esophageal junction cancers, there remains unmetneed in advanced HER2+ cancers, where efficacyis lower and fewer agents are approved; as well asin diverse HER2+ cancers (for example, metastaticlung, ovarian, colon and bladder cancers), for whichthere are no approved targeted agents. HER2 hasseveral advantages as a target antigen for CAR-M.In addition to being expressed in a variety of solidtumor types with a significant medical need, HER2is not shed or internalized and is only expressedat low levels in non-tumor tissues. Because HER2expression is typically maintained over the courseof disease, CT-0508 is expected to be effectiveagainst metastatic disease, for example, in liverand lung, as well as primary tumors.

In addition to establishing the safety of the vec-tor-transduced CAR-M cells administered intra-venously, the phase 1 study will incorporate read-outs to validate all aspects of CAR-M’s proposed

mechanism of action, including trafficking to tumor(assessed via PET imaging and post treatment biop-sies), tumor phagocytosis, expression of multiplecytokines and chemokines and cell recruitment,conversion of TAMS to a pro-inflammatory M1state, and epitope spreading via T cell activation.

Partnering for progressIn anticipation of the phase 1 trial, good manufac-turing practice (GMP) cell product manufacturingmethods and partnerships have been put in placefor all components, including Oxford Genetics forplasmid production, Wuxi for vector assembly andMiltenyi for primary cell manufacturing. Carismais actively seeking additional alliances to supportlate-stage clinical and commercial activities inoncology, including two additional programs inmesothelin- and prostate-specific membraneantigen (PSMA)-positive cancers, and otherundisclosed oncology targets.

Further partnerships are envisioned to extendCAR-M therapy to additional therapeutic areas:in neurodegenerative disease, such as Alzheimerdisease and Parkinson disease, CAR-M are beingdeveloped to specifically target and clear aggre-gated pathogenic proteins. Similarly, CAR-Mengineered via nonviral methods can be directedto develop an M2, immunosuppressant phenotypethat holds promise for multiple diseases character-ized by inflammation and fibrosis.

Pathogen

Antigen Chimeric antigenreceptor Cytokine release MHC protein

The activated T cell can recognizepathogens and establish long-

term immunity / memory

Trafficking and phagocytosis

Dendritic cells

T cells Antigenfragments

1 2 Immune activation 3 Antigen presentation

ActivatedT cell

T cell

Macrophage

Fig. 1 | The unique mechanism of action of chimeric antigen receptor macrophage (CAR-M) therapies.MHC, major histocompatibility complex.

Tom Wilton, Chief Business OfficerCarisma TherapeuticsPhiladelphia, PA, USATel: +1-267-491-6422Email: tom.wilton@carismatx.com

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www.nature.com/biopharmdeal | September 2020 | B33