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D. Qualls and G. Salles
Phagocytosis checkpoint inhibitors
Macrophage-mediated phagocytosis is modulated by a series of checkpoints including the CD47-SIRPa check- point, classically known as the “don’t eat me signal.”96 Immunotherapies inhibiting this interaction facilitate macrophage activation and phagocytosis, and show prom- ise in FL. Magrolimab, a humanized IgG4 isotype that binds CD47 and blocks interaction with SIRPa, was evalu- ated in combination with rituximab in a phase Ib/II study of relapsed/refractory indolent non-Hodgkin lymphoma (28 of 29 patients with FL), with an overall response rate of 66% and a median duration of response not reached (range, 6.2-22.6 months).97 Toxicities included infusion reactions and a class toxicity with first-dose anemia, relat- ed to splenic phagocytosis of senescent red blood cells. Other CD47-targeted agents such as ALX148 and TTI-622 have also demonstrated activity in FL.98,99 In the preclinical setting, bispecific antibodies targeting CD47 and CD19 have been designed to increase drug specificity and decrease on-target, off-tumor toxicity.100 Outside of the CD47-SIRPa axis, inhibitors of adenosine receptors have been shown to disinhibit antibody-dependent cellular phagocytosis, and show promise in preclinical studies.101
As with other agents, there is increased interest in com- bining magrolimab or alternative pro-phagocytic agents with other immune therapies. A study showed that T-cell deficiency in mice abrogated the response to anti-phago- cytic agents, and suggested that CD8+ cytotoxic T cells
play an important role in the mechanism of action of pro- phagocytic therapies.102 CD47 blockade also enhances the ability of dendritic cells to cross-prime T cells.102 Given these findings, there is a mechanistic rationale for the addition of a checkpoint inhibitor or T-cell co-stimulatory agent to anti-CD47 therapy. There is also in vitro evidence that chemotherapy administered prior to phagocytosis checkpoint inhibitors improves tumor response and aug- ments host memory response against relapsing tumors. Further studies of combination therapies are needed, as well as a better basic understanding of the interactions between the innate and adaptive immune responses to lymphoma.102
Checkpoint inhibitors and T-cell co-stimulatory agents
The immune infiltrate in FL is enriched in PD-1-positive immune cells, suggesting that immune tolerance plays a key role in lymphomagenesis, and that disruption of these signals via checkpoint blockade would be effica- cious.103 Prior studies have investigated mechanisms of T- cell rescue via checkpoint blockers targeting the PD-1/PD- L1 axis.104-108 While preliminary data suggested encourag- ing response rates from this treatment in combination with anti-CD20 monoclonal antibodies, no definitive benefit has been established, and single-agent activity has been disappointing, with response rates of 4-9%.
There has also been interest in the utility of co-stimula- tory agents in T-cell reconstitution and immunotherapy.
Table 3. Selected pivotal trials in relapsed or refractory follicular lymphoma.
Targeted agents
Parsaclisib
Zandelisib Ibrutinib
Zanubrutinib
Tazemetostat Abexinostat
Immunotherapies
Magrolimab Mosunetuzumab
Tafasitamab Tisagenlecleucel
Other
(177Lu)-Lilotomab satetraxetan
Loncastuximab tesirine
Mechanism
PI3K d inhibitor PI3K d inhibitor
BTK inhibitor BTK inhibitor
EZH2 inhibitor pan-HDAC inhibitor
Anti-CD47 MoAb
Anti-CD20 x anti-CD3 bispecific antibody
Anti-CD19 MoAb Anti-CD19 CAR T
Radiolabeled (177 Lutetium) Anti-CD37 MoAb
Anti-CD19 antibody drug conjugate
Phase Drugs
III Parsaclisib + anti-CD20 vs. Anti-CD20 monotherapy
II Zandelisib monotherapy
III Ibrutinib + R-CHOP or BR vs. R-CHOP or BR
III Zandelisib – rituximab vs. R-CHOP or BR
II Zanubrutinib + obinutuzumab vs. (randomized) Obinutuzumab
III Tazemetostat + R2 vs. R2 II Abexinostat monotherapy
II Magrolimab + rituximab
III Mosunetuzumab + lenalidomide vs. Rituximab + lenalidomide
III Tafasitamab + R2 vs. R2 II Phase II study (ELARA)
IIb (177Lu)-Lilotomab satetraxetan
II Loncastuximab tesirine vs. Idelalisib
Prior lines of therapy
N. of planned participants
≥1 416 ≥2 180
≥1 403 ≥1 534
≥2 210
≥1 518 ≥3 139
≥1 422 ≥1 400
≥1 618 ≥2 97
≥2 204 ≥2 150
Status
Not yet recruiting
Recruiting Active, not recruiting
Recruiting Recruiting
Recruiting Active, not recruiting
Recruiting Not yet recruiting
Recruiting Active, not recruiting
Recruiting
Recruiting
NCT #
NCT04796922
NCT03768505 NCT01974440
NCT04745832 NCT03332017
NCT04224493 NCT03600441
NCT02953509 NCT04712097
NCT04680052 NCT03568461
NCT01796171
NCT04699461
This list is not exhaustive but outlines the agents discussed in the review. NCT: National Clinical Trials; PI3K: phosphoinositide 3-kinase; BTK: Bruton tyrosine kinase; R-CHOP: rit- uximab, cyclophosphamide, doxorubicin, vincristine, prednisone; BR: bendamustine and rituximab; EZH2: enhancer of zeste homolog 2; R2: rituximab and lenalidomide; R: rit- uximab; HDAC: histone deacetylase; MoAb: monoclonal antibody; CAR T: chimeric antigen receptor T cell.
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haematologica | 2022; 107(1)