A New Attack on Blood Cancer

The scientists and startups hunting ROR1

Unlike common cancers of older age — liver, pancreatic, lung — blood cancers can get you early.

Leukemia and lymphoma emerge from your bone marrow or your lymphatic system and into your bloodstream, where the thumps of your heart drive the malignant cells throughout your body.

Fatigue, weakness, swollen nodes—by the time you notice, it’s often too late.

ROR1 is a promising new therapeutic target: a protein abundant on the surface of cancer cells but rare on healthy cells. A wave of experimental drugs exploit this difference to kill cancer without harming normal tissue.

Scientists at several startups and research institutes are pursuing four key strategies to bring ROR1-targeted therapies to patients.

By 2015, ROR1 was known to be fairly specific to cancer cells. The Kipps Lab at UCSD designed a monoclonal antibody (mAb) called cirmtuzumab, which binds onto ROR1 and initiates a biologically-encoded cell-killing routine.

The Kipps Lab tested cirmtuzumab against cells from patients with chronic lymphocytic leukemia (CLL), the most prevalent blood cancer in adults. Cirmtuzumab triggered innate biological systems to kill most of the cancer, while healthy cells were spared.

This marked progress over the former leading mAb in CLL, Rituxan, which kills cancerous and healthy cells alike. Rituxan extends life expectancy for CLL patients, but its potential side effects result in a max dose that limits efficacy.

The Kipps Lab licensed cirmtuzumab to Oncternal for clinical studies. After a good phase 1 trial, the mAb has entered a phase 2 trial with data due in 2022.

As ROR1 is expressed by certain non-blood cancers, Oncternal has also begun a phase 1 trial against breast cancer, combined with standard chemotherapy.

Along with cirmtuzumab, Oncternal is also developing an anti-ROR1 CAR-T.

CAR-T is a powerful class of immunotherapy already approved by the FDA against another blood cancer protein. CAR-T therapies, in which a patient’s immune cells are genetically enhanced against cancer, are in trials for several drug targets and cancers, with higher effectiveness than mAbs like Rituxan.

CAR-T therapies are highly effective but challenging to manufacture [L&LS].

Whether ROR1-focused CAR-T will outperform cirmtuzumab is uncertain. Oncternal’s CAR-T is still preclinical. The other anti-ROR1 CAR-T—from the Riddell Lab at the Fred Hutchinson Cancer Research Center and the Rader Lab at the Scripps Research Institute—is in a phase 1 trial with key results in 2021.

As CAR-T requires drawing a patient’s blood, genetically engineering the blood’s immune cells, culturing the cells for weeks, and infusing the cells back into the patient, it’s costly, difficult, and only viable in certain patients.

The Riddell Lab also showed in a 2019 mice trial that lymphodepletion before CAR-T can render therapy lethal, a risk being monitored in the phase 1 trial.

Many risks of CAR-T can be mitigated with bispecific T-cell engagers (BiTEs).

BiTEs are antibodies with two ends (unlike mAbs such as cirmtuzumab). One end grabs a protein on the cancer cell (in this case ROR1); the other end grabs a protein on immune cells (usually CD3).

By bringing cancer cells and the immune cells into close proximity, BiTEs induce immune cells to tear open pores in the cancer cell membranes and insert signals that trigger a suicide switch within the cancer cells.

This BiTE binds to ROR1 on cancer cells and CD3 on immune cells. [Fig 1A, Qi et al. 2018]

Unlike CAR-T, BiTEs don’t require drawing and modifying the patient’s blood. Instead, like mAbs, BiTEs can be immediately infused and work rapidly. Also, as BiTEs don’t follow lymphodepletion (again unlike CAR-T), that particular risk discovered at Fred Hutch is unlikely to be an issue.

There are two anti-ROR1 BiTEs in early-stage R&D:

The first, created by the Nathwani Lab at University College London in 2017, has been out-licensed to an undisclosed company for further development.

The second, engineered in 2018 by the Rader Lab at Scripps with improved molecular properties, is still undergoing iteration prior to preclinical trials.

In addition to the UCSD mAb; the CAR-Ts from Oncternal and Fred Hutch; and the BiTEs from UCL and Scripps; NBE-Therapeutics is developing an antibody-drug conjugate (ADC) against cells with ROR1 on their surface.

Similar to BiTEs and cirmtuzumab, ADCs use an antibody to bind to proteins. However, rather than trigger cell death directly or prime anti-cancer immune cells, ADCs carry a toxic molecule conjugated to the antibody. When the ADC reaches the intended cancer cell, the toxin is absorbed and kills the cell.

One downside to ADCs is that the toxic agent may be released early, or in the wrong place, poisoning nearby healthy cells rather than the malignant goal.

The ADC from NBE, which is also based on work by the Rader Lab at Scripps, will be tested for safety and initial efficacy in a phase 1 trial starting in 2020.

Which of these four strategies — mAb, CAR-T, BiTE, or ADC — will be the most effective against cancer? While we’re still years from definitive data, my guess is that BiTEs like the one from the Rader Lab will yield the highest utility.

BiTEs combine the convenience of regular antibodies with the strong immune activation of CAR-T, while avoiding the lymphodepletion threat discovered by Fred Hutch and certain side effects that have restricted the success of ADCs.

However, BiTEs are the most novel tactic among the four, so while the BiTE approach appears promising now, there may be unanticipated pitfalls ahead.

Blue: early-stage cancer. Red: late-stage cancer. Mice given placebo (left, vehicle) were terminally ill within a month, but mice given the Rader Lab BiTE (right, R11 x v9) were completely cured. [Figure 5A, Qi et al. 2018]

One critical risk for the entire field of ROR1-targeted drugs is the presence of ROR1 among a subset of healthy cells. While much more common on cancer cells, ROR1 has been detected in the pancreas, the stomach, and elsewhere.

What happens if a BiTE or CAR-T redirects the immune system against benign cells—or an ADC releases its toxin in a healthy part of the body by mistake?

To ameliorate off-target risks, the Fred Hutch team has engineered a CAR-T that must detect both ROR1 and a second cancer protein before activation, but the added complexity of this logic-gated system may reduce its efficacy.

Whether such techniques will be necessary should become much clearer as clinical data emerges from phase 1 and 2 trials over the next few years.

In the meantime, if you’re working on an ROR1 program that hasn’t been published yet, or if you have any questions or comments, please email me.


Principal at RA Capital, on the boards of 7 biotech companies. Founder/CEO of Nivien Therapeutics. Australian-American. 50 countries and counting.

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